So, you want a make a sprite comic? Like most people think, making a sprite comic is easy. Making a good one, not so much. A lot of people will just grab whatever sprites they can find, throw them together into an ugly mess, and call it a comic. However, if you want to make something good, the work begins long before you start dropping sprites onto a background. It begins with a plan.

Step 1: Why am I Making a Comic?

This is a good question to ask yourself at the get go. If you don't have a good reason you might not have the motivation to keep working on your comic, especially if things don't go the way you hoped. Here are a few common reasons.

WRONG REASONS
"I want to make lots of money.": Not good. If you're only in it for money, you probably won't put enough effort, heart, or personality into your comic, something that will be quickly noticed by readers. In addition, the chances of you ever making money off your comic are tiny. Only a few of the most popular comics make enough money to support their creators. In general, you'll be very lucky if you get enough cash to pay off your hosting and domain fees.
"I want to be popular.": Once again, if this is the best reason you can come up with, your work is going to suffer. Also, very few web comic authors become even remotely famous.
"Because it's easy.": Ok... Sitting on the couch watching TV is even easier. Why don't you just go do that instead?

RIGHT REASONS
"I want to tell a story.": That's good. The desire to tell a good story will help keep you motivated and keep you interested in your comic.
"I want to expand on a favorit game.": Lots of great games, espeically older ones, have very little plot. Adding some intrigue and personality to them can be a lot of fun.
"I want to have fun.": Making a comic can be a lot of fun. However, it can also be a lot of work so make sure you keep that in mind.

Step 2: Choosing a Subject & Style

Figured out your reason? Good. Now it's time to decide what your comic will be about. The first question should be are you parodying and/or expanding on an existing game or creating an original story? If you want to make a sprite comic, chances are you have at least some idea of what you want to make. Spend some time thinking about. How will it start? Where will it go? What will the characters be like? Try to run through a few scenes in your head to see how they work.
Another important question to ask yourself is has it been done before? Or possibly, has it been done before well? There's no point in simply rehashing what's already been done well, no matter how much you like it. For example, say you want to do a comic about the game Star Tropics. As far as I know, there aren't any Star Tropics comics out there so you'd be pretty safe. On the other hand, say you want to do a comic about Mega Man. Now that's a little iffy, there's already a lot of Mega Man comics out there. That doesn't mean you can't do one, it just means that, if you want your comic to stand out in the crowd, you have to do it a bit differently. Don't just make another Bob & George clone where Mega Man is an idiot, Dr. Light is a drunk, the robot masters have quirky personalities, and the like. Instead take an approach that hasn't already been done to death. Maybe do a serious Mega Man action series, or a mystery, or whatever. Just don't do what everyone else has already done. Bob & George has already done a great job with the whole Mega Man is an idiot style and if you try to do the same thing you'll just end up with a lot of unfavorable comparisons.
If you're doing an original story this is a bit less of a problem but even so, be careful. If there's already a popular well established comic doing something similiar you may have a hard time getting fans.
Before you make a final decision do a little research. Check out popular comic lists (Top Web Comics, Buzz Comix, etc), Google, and the like to see what else is out there.

Step 3: Choosing a Format

At this point, you may want to spend a couple minutes making sure that you want to do a sprite comic. Perhaps your comic could work well as a hand drawn comic, a pixel art comic, or some other style. There's nothing wrong with sprites, but make sure you at least spend a few minutes considering your options.

Once you've decided on an art style you need to pick a layout. Here's some of the more common ones.

4 Panel Strip: This popular style is used in many comics including Pebble Version and Bob & George. It's based on the layout of newspaper comic strips and it easy to set up and break into scenes. You can also combine some or all of the panels to make longer panels. However, its size and shape can be a bit limiting if you want to do something fancy. Also, you need to make sure that you can make a good scene and/or joke in only four panels.
4 Panel Square: This is similiar to the 4 Panel Strip except that it's a 2 panel by 2 panel square. You can combine panels to get more height but you can't do really long panels like you can with the 4 Panel Strip.
Full Page: Used by comics like 8-Bit Theater, having a single big page to work with gives you a lot of freedom when it comes to the size and arrangement of your panels and you can easily change things around to suite your comic strip. However, because of that freedom this format takes some getting used to and can be difficult to work with.
There are many other layouts too so think about it and play around a bit till you find one you like.

Finally, choose a perspective. For example, are going to be looking at the scene from the top? The side? An angle? If you're basing your comic on a video game you may want to choose the same style that the game uses. For example, Mega Man games are viewed from the side and Zelda games are viewed from the top at a bit of an angle. Matching your perspective's with the game your sprites are from is easy and ensures that the sprites will look good at that perspective. However, don't feel like you have to do things that way. For example, Pebble Version mostly uses a side view despite the fact that the Pokémon games use an angled top view. 8-Bit Theater also uses a side view even though Final Fantasy mostly uses a angled top view. As long as the sprites look ok, you can use any angle you like.

Conclusion:

Once you've gone though the steps listed above you should have a much better idea of what type of comic you're going to make. Don't be tempted to just skip the planning phase. Your comic making experience will be much smoother if you figure all this stuff out now instead of waiting till after you've already started making strips. So take some time, give it some thought, and keep an eye out for Josiah's Sprite Comic Guide Part 2: Finding and Collecting Your Sprites.