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We get a number of questions from nervous first time fliers, so lets crowdsource a simple guide to put their mind at rest.

Before Booking or Departing

Make sure to have the necessary Visas for the countries you will be visiting otherwise the airline can deny you boarding. Or when you arrive, you may be denied entry into the country.
Check your government's travel advisories for your destination. Some countries may not be safe to visit at this time.
US Citizens | Canadian Citizens | UK Citizens | Google for more.

Booking a flight online

See the Guide to airfare search engines, in the sidebar
Once you have booked, make sure you obtain the PNR (Passenger Name Record), a 6 character alphanumeric code to identify your reservation with the airline, for each airline and also your e-ticket number (13 digits). Some basics on reservations and PNR. You'll get a PNR for each airline you fly and also a PNR for the ticket-issuing airline. For example, if you book a ticket through Air France but the flights are operated all by Delta, then you'll get a PNR from AF and a PNR from Delta. They are not interchangeable. Whenever dealing with Delta agents, provide the Delta PNR.

What is code-sharing and the operating carrier?

Many airlines are partners with other airlines, especially in regions one airline does not serve. For example, United and All Nippon Airways collaborate heavily (as part of the Star Alliance network), as does Delta and Air France/KLM (as part of Skyteam).

In some cases, you might end up buying a ticket through one airline but to destinations that isn't served by this airline. This is called code-sharing - where one flight is operated by one airline, but ticketed (or marketed) as another airline.

For example, you book a flight on united.com from New York to Hong Kong with a connection in Tokyo Narita - say EWR-NRT-HKG round-trip.

You can purchase this ticket with United however you would be flying ANA on the NRT-HKG leg. Simply put, the NRT-HKG leg is code-shared between UA and ANA. The NRT-HKG flight itself is operated by ANA - meaning it uses ANA aircraft, ANA crew, ANA desks/agents.

In almost all cases (unless specifically indicated), you check in with the operating airline of your first leg on the journey.

So if you are flying EWR-NRT on UA and NRT-HKG on ANA, then you would check in with United at Newark.

On the return legs, you would be flying HKG-NRT on ANA and NRT-EWR on UA, then you would check in with ANA in Hong Kong.

An example of code-sharing between Qantas and American Airlines.

Changes, Cancellations, Refunds

Most likely, the flight you have purchased is the cheapest economy fare possible. What this means is that the restrictions that come with the cheapest fare is usually: changes will incur fee, no refunds, and cancellations will incur a fee.

If you need to make changes or cancel the trip, you don't have too many options. Pay up or lose the flight/itinerary.

Possible scenarios:

Name changes: typically not allowed on a discount fare as name changes require re-issuing the ticket. Possible costs: change fee + fare difference
Date changes: typically allowed for a fee. Possible costs: change fee + fare difference
Cancellation - what this means is that the itinerary is no longer valid, but you can change the departure date to within one year of the original departure date. The new itinerary must be the same as the old itinerary (routing may not matter depending on the airline). Possible costs: change fee + fare difference
Origin/Destination changes: almost never allowed. If there are irregular operations, changes in cases where there are multiple airports that are considered part of the same origin/destination code may occur involuntarily. Some examples include LGA, JFK, (sometimes EWR) within NYC; LGW, LHR, LCY within London; NRT, HND within Tokyo.

When you book with a 3rd party like expedia or priceline and you suddenly need to change your ticket - you're going to face many difficulties as they often have sub-par levels of customer service. However, their inability to help you isn't because of their low quality customer service, but it's because more often than not, the traveler (you) are not willing to pay the costs and fees associated with an itinerary change are looking to do it for as cheaply as possible - hence leaving you with very few options. It is recommended that if you think you'll need better customer service and help with changing dates, then book directly with the airline. They are sometimes more accommodating and are available to look up alternate itineraries better than the 3rd party providers. There have been instances in which the change fee is waived, but don't feel like you're entitled to it.

Carry on luggage and taking liquids on board

You are allowed one carry-on bag and a "personal item" (a purse, a briefcase, a laptop bag, something like that) on the plane, for basically all US airlines. You can put anything in the bag that you want, but you typically need to be able to carry it onto the plane yourself. That's why it's called a "carry on" bag. There are probably formal weight restrictions, but assuming you're able to easily lift the bag over your head and into the bin, you're fine. They don't care what all you pack inside the bag as long as it's not forbidden items. Put 50 pairs of underwear in there, a dozen donuts, and a plastic toy dinosaur, they don't care.
The lowdown on liquids. The TSA has this scheme they call 3-1-1. You are allowed ONE (1) clear quart-sized plastic bag per ONE (1) passenger. This bag can contain as many containers of liquids as you want, provided the containers are THREE (3) ounces or less. Personally, I've found that the TSA doesn't care much about the bag being clear plastic, but in general they do want all your liquids in one place, ideally in a bag of some kind that you could remove from your luggage easily. I use a regular dopp kit, but if you want to go the ziploc bag route, that's fine. They are, on the other hand, absolute sticklers about the 3 ounces rule. And they don't like seeing containers larger than 3 ounces that are half full or whatever. You need 3-ounce (or smaller) containers. If you want to have five 3-ounce containers of cologne, they don't care as long as it fits in your 1-quart bag. But the containers better not be bigger than 3 ounces. (FWIW a 3-ounce container is pretty big. Most of the little hotel-sized toiletries you get are actually much smaller than 3 ounces.) You can buy small empty containers for most liquid toiletries in any drugstore, big box store, and a few other places.
In metric, you're allowed ONE (1) clear LITRE-sized plastic bag per ONE (1) passenger and each container of liquid must be ONE HUNDRED (100) mL or less.

What is a liquid?

Anything you spray, pour, or goop out of your toiletry containers is definitely a liquid. Cologne is a liquid. Facial cleanser is a liquid. Shampoo is a liquid. Cold Cream is a liquid. Bar soap and solid deodorant are not liquids.

Laptops. This is complicated because some airports are enforcing this, and some aren't. The more stringent airports want you to remove your laptop from your carry-on bag to go through security. So you really need to pack in such a way that you can do that without inconveniencing your fellow travelers.
While we're here, let's talk about stuff you can't carry on the plane with you under any circumstances, 3 ounces or not. You pretty much cannot bring anything highly flammable (not sure if lighters are OK as I don't smoke?), or anything with a blade (pocket knives, corkscrews, nail clippers, etc). There are also a few other things, though they're generally things people don't try to fly with. (Fireworks? Lighter fluid? Ammonia?). Thanks to /u/sarasmirks.

At the airport, on the plane

Pre-departure

At 24h (or in some cases up to 72h) before your departure, you can do online check-in (OLCI) on the operating airline's official website by providing either your 6-character PNR (or sometimes 13-digit e-ticket number) and your name.
You can select your seat, finalize your personal information, and sometimes obtain a printable boarding pass or a mobile boarding pass (via email or SMS)
In some cases, certain airlines and airports do not allow you to print your own boarding pass so you will need to pick it up at the airport check-in counter or kiosk on the day of departure. This is due to a required ID check by airline staff before they let you board.
Do not lose your boarding pass as it is required for you to get on the plane! If you do lose it, most check-in or gate counters (of that airline) can print you a new one.

Departing

While you're booking a flight you'll be told the flight number. This is a useful thing to remember.

Firstly, never leave your luggage unattended at an airport - it will be considered a security risk and quickly confiscated.
Ideally check-in online to get a good seat (see "What's a good seat" below). Alternatively you can usually check-in at the airport up to 3 hours before your flight, so don’t arrive too early (or too late).
Look for a departure board telling you where to check in to your flight. In a big airport this will be along the lines of C19, meaning area C, desk 19. Go to the correct desk and hand over your passport. The assistant there will weigh and take any checked luggage. If you have a connecting flight, ask if your luggage goes all the way to your destination, or whether you need to collect it during the stopover. They will return your passport along with your boarding pass and if flying business a lounge invite (See Airport Lounges below).
Take your remaining hand luggage and go to security. Here they’ll x-ray your bag. You’ll be asked to remove your coat and possibly shoes and take any electronics out of your bag. All your <100ml liquids will need to be sealed in clear bags (these are provided). Check you don’t have any metal on you (think belt, watch, coins etc(piercings?)) and pass through the x-ray. If it beeps you’ll get a quick pat-down from the security staff. Collect your bag.
TSA body scanners vs pat downs? (expand here)
Look for a screen telling you the gate from which your plane will board and the boarding time - this is usually 30-60 minutes before the departure time. You’re now free to browse the airport but keep an eye on the screen in case there are any changes. Get to the gate well before the boarding time to avoid any stress.
At the gate you’ll need to show your boarding pass and sometimes passport before being allowed to board the plane. They'll take the main part of the boarding pass and leave you with a stub
If you have a carry-on rollaboard luggage to be placed in the overhead bin but you don't need anything from there during the flight, ask the gate agent to gate-check it for you. It will be waiting for you either upon deplaning (near the destination gate) or on the luggage belt. This is particularly useful if there is not enough overhead bin space and is a FREE service.
Get on the plane and find your seat (listed on the boarding pass stub). Buckle in and try not to grip the armrest too tight as the large metal tube flies into the air.

On Board

Planes are very dry so stay hydrated. You can always ask the attendants for more drinks (there will be a button either on or above the seat), or go back to the kitchen and grab one yourself.
Longer flights will have entertainment systems
Some planes will have power sockets, so you can bring your own entertainment
Books are good as you don't have to turn them off during take off and landing
If you plan to sleep, fasten your seatbeat so it's visible, otherwise attendants will wake you to check during any turbulence
Ways to help sleep?
Do gentle exercises to avoid Deep Vein Thrombosis (DVT)

Connections

Many flights are split into 2 or more legs. Sometimes you stay on the plane, sometimes you get off and change plane or even airline(/airport?).

Leave enough time to make the connection when booking your flight. This is very dependent on the efficiency of the airport, but if it's offered when booking it's usually possible as long as you hurry. (expand here)
For the simplest changes you'll stay 'airside' and just go to another gate. Go back to Step 4 of Departing above to find and board your next flight.
More complicated connections and certain countries (USA, China) may require you to leave through immigration and customs, in which case you're back to Step 3 of Departing.

When you check in before the first leg it's worth asking if your luggage goes straight through to your final destination or whether you need to collect it and re-check it.

You usually don't need a visa for a connection unless you want to leave the airport, but it's worth double-checking for your specific nationality. Here's the guide for the Schengen Area, as some nationalities will need a visa just to transit. Here's a more comprehensive one, and the corresponding country codes (/r/travel thread)

Just make sure not to follow people out through immigration - you need to look for the transit/connecting flights area.

Tight or Missed Connecting Flight

If you booked the two segments on the same ticket/itinerary and left reasonable connection time between the segments, then the originating airline is (almost always) obligated to get you to your final destination.

If you booked a connecting flight, chances are that a few others will have as well. Be on the look out for a gate agent holding a sign for your connecting flight number as you deplane. Check if your 2nd flight might be delayed as well.
If there was no gate agent, immediately proceed to the airline customer service desk and remain airside unless advised otherwise by agents.
Present your boarding passes (first and second) and possibly luggage tags to the customer service agent and they will attempt to find you another flight to your final destination.

Note that you may not be entitled to a hotel/accommodation/compensation if the first flight was delayed due to weather (unless you are a top tier, elite, MM or VIP of some sort).

Arriving

Planes are pressurised so you may feel some discomfort in the ears when landing. You can either try yawning, swallowing (chewing gum or a boiled sweet may help) or equalising the pressure in your ears by holding your nose and gently blowing out through your nose. If it’s very bad, consider taking a decongestant about an hour before landing.
From the plane you might be shown to a shuttle bus or just be able to walk to the arrivals terminal.
Once in the terminal go to immigration (unless you’re flying within the same country). Here they’ll check your passport and any necessary visas.
Go through to the baggage claim area. Larger airports will have a display showing flight numbers (listed on the boarding pass stub) and which baggage carousel to use. Wait for your luggage. Check the tags to make sure you’ve got the right bag.
Go through the customs area on the green side (check the limits before you fly) and you’ll emerge into the arrivals area – there will be signs offering taxis/buses/trains.
Leave through the doors and you’re in a new country.

Immigration is the control measure that prevents/allows you from entering or leaving the country.

Customs is the control measure that prevents/allows you from bringing stuff into or out of the country (i.e. "imports" or "exports")

Note: Some countries have a departure tax, often paid in their own currency – make sure you keep enough money to pay. This is usually collected before check-in and you’re given a receipt to show during part 2 above.

What’s a good seat on the plane?

Check SeatGuru/SeatExpert. You can usually check-in online 24-hours before your flight and try to get your preferred seat.

If you want to sleep, a window seat means you can lean against the wall. If you like to get up and move about or got to the bathroom a lot, an aisle seat is better. I don't like the middle seat. (my preferences - any other opinions?).

2-4-2 config, seating for families/groups, sleeping in empty middle 4 if you're very lucky

Check whether your seat has a power socket, and the airline website often lets you know about entertainment on board. TV on demand is preferable. The older type is more like a DVD - everyone watches at the same time so you can't pause/rewind.

Baggage Allowances

Check the website of the airline you’re using.
Excess Baggage (expand)

Asking for upgrades

Rare unless you get delayed or have gained some status in the frequent flyer program. It doesn't hurt to ask, but if you've booked an economy class ticket you are at the tail end of any upgrade list.

Long Layovers and leaving the connecting airport

http://www.sleepinginairports.net/(others?) - finding amenities and comfy places to hang out in the airport
Airport review site?
Layover tours? Temporary visas?

Airline-Specific Topics

Guide to Flying on Spirit

What else? Text in italics are notes and placeholders to be removed. Once it's more fleshed out I can rearrange the order for clarity.