Foldit can be an extremely confusing game. The Foldit Wiki has not always been the most helpful in cutting through the confusion. After a burst of enthusiasm after its creation, the wiki fell into a sudden flurry of inactivity sometime after 2011. Paul Dunn has provided most of the new content for years now, posting the puzzle results shared by other players. Please keep in mind that this wiki is a 100% volunteer effort.
The fold.it site has a new 2017 forum post How to Get Started Playing Foldit!, which replaces the original 2010 version. Take a look at that post first, then check out the additional details here.
Foldit runs on Windows, Mac, and 64-bit Linux. (The CPU-intensive nature of the game means it will probably never run on a phone or tablet.)
Please report any trouble installing the game to the Foldit feedback page. Select "Crash/Hang" for the topic, and "Bug" for the type. You'll have to register as a Foldit user to post a feedback, but you'll need to do that anyway. See the discussion of registration below.
Assuming the install step goes smoothly, the first thing Foldit does when it starts is to download the latest updates. This can take a while, but after the first time, big downloads happen only a few times a year.
After it updates itself, the Foldit client restarts and asks you to log in. This is another spot where you'll need to be registered to participate.
Foldit does have a "play offline" mode (ugh), but to really experience the game you need to register and play online. Registration is mostly harmless, via the Create New Account link on fold.it.
Consider the Foldit Community Rules when selecting a user name. A lot of primary and secondary school groups play the game, which means the game needs to be PG-rated (in American terms). Strangely, the presence of these lil' darlin's is one of the biggest challenges to maintaining that PG rating. We did have a player named Colostomy EXPLOSION. active for a couple of years, which was pushing the limits just a little. Try to pick a name that would seem clever 10 years from now, if you're applying to grad school and your contributions to the game happened to be cited in a scientific paper.
While you don't have to complete all the intro puzzles, you'll probably find the rest of game a little less confusing if you do as many as possible. Some Linux users have reported repeated crashes with one of the intro puzzles. Unfortunately, you can't skip forward in the intro puzzles, although you can always go back.
The real secret of the intro puzzles is that you don't have to complete all them before starting on regular Foldit puzzles. Just look for the "Main Menu" link, then take a look at the "Science Puzzles".
There are six Beginner Puzzles available at all times. These puzzles run in rotation for six weeks, and only players with less than 150 global points receive points for playing them. They're a good way to go beyond the very limited intro puzzles.
Aside from the beginner puzzles, there's always a revisiting puzzle running. Revisiting puzzles were originally presented in the early days of Foldit. Most have been revisited several times since then. Revisiting puzzles are mainly a way for the Foldit science team to evaluate the impact of changes to the game, but they're still fought over as intensely as any other puzzle.
Aside from the beginner puzzles, most regular puzzles run for one week. If you're concerned about your ranking, these puzzles are a quicker way to get points. (You're guaranteed one global point just for opening a puzzle.)
You'll also see Contests. Contests are created by Foldit players, and use a fixed set of proteins, although they do include proteins which can be designed. Unlike puzzles, contests don't award global points, and can run for years. They can be useful to things like testing recipes, but almost all the attention goes to tthe regular Foldit puzzles.
When you first install Foldit, your cookbook contains four recipes, which are examples of the original "GUI" recipe. These samples are not very useful. Some puzzles used to allow only these GUI recipes, but we haven't had any puzzles of this type in quite a while.
The more powerful recipes are written in the Lua scripting language, which is also used in Angry Birds and World of Warcraft.
One of the most powerful and most useful recipes in Foldit is Timo van der Laan's Tvdl enhanced DRW 3.0.1, better known as EDRW, which applies the Rebuild tool to the worst-scoring sections of the protein. It's several thousands lines of Lua code, which have helped to create countless other recipes. Recent design puzzles have eliminated Rebuild in favor theof remix tool, so there's TvdL DRemixW 3.0.0 for those puzzles.
In the early phases of folding, you may want to have a "fuse" or maybe "fuze" recipe, which stabilizes the protein by varying the Clashing Importance setting (CI) while wiggling and shaking. Rav3n_pl Fuzes v1.5.1 is a useful "fuze", but there are many others.
The Rebuild and Remix tools work by taking shapes from known proteins. Random exploration is also an important part of Foldit. There are various "compressor" recipes, which use random sets of bands to attempt to improve the score. These recipes led to the "GAB" or or "Genetic Algorithm Bands" family of recipes, which attempt to improve on bands which increased the score. Rav3n_pl GAB BiS Filter v2.2.3 is one of many GAB recipes.
For design puzzles, many recipes, including EDRW, mutate the amino acids as part of what they do. Other recipes focus on mutating, for example Mutate No Wiggle 1.2 -- Brow42, which even skips shaking and wiggling the protein in favor of trying as many mutations as possible.
Toward the end of a puzzle, many players use a variation of the Local Wiggle Strategy to make small improvements to the protein. Banded Worm Pairs Inf Filt 1.3 is one example of a local wiggle recipe, which uses bands to help keep things moving.
Having good recipes is an important step. There are a few other things which can help you fold like a pro. (However, there are no professional Foldit players, as far as we know.)
Switching to the Advanced GUI is highly recommended for all users. Lately sounds have been disabled in Foldit, but if the annoying music is back, you can turn it off in the same control+T general options menu where you select Advanced GUI.
Advanced GUI gives you many more View Options, among other things. In view options, it may be a good idea to turn off settings like "show clashes", "show voids", "show exposeds", and "show sidechains with clashes or exposeds" to get a better view of the protein. You may want to turn off sidechains when not needed using the "don't show" view option (or the shift+D keyboard shortcut). Drawing all those sidechains can really slow down the game.
Foldit has two game interfaces. The original interface is what you see in the Intro Puzzles. There's also the Selection Interface, where the tools available depend on which segments are selected. The selection interface can do some things the original interface can't, but many top Foldit players have stuck with the original interface.