If you're trying to see independent films or foreign films, I recommend the Landmark group of theaters: Embarcadero Cinema, Bridge Theater, Clay Theater, Opera Plaza, and the Lumiere. They lack some of the amenities of the bigger theaters, but chances are if you're looking for an exceptional film that isn't necessarily a blockbuster, you'll find it at one of these. I also love the Roxie for the same reason--they play films that simply aren't distributed in other theaters. I also second the recommendation for visiting the Castro where the whole experience is like a special occasion thanks to the gorgeous interior and organ performances. For new releases and blockbuster films, I have come to really like the Century San Francisco Centre at Westfield Shopping Mall. It's nice and new, and every seat in the house has a great view of the screen.
If you are into comfort and amentities, I would recommend the Sundance Kabuki Cinema on Post Street. There's a bar that offers food and drinks (you can take them with you in the theater) and, at least for the main theater, you can reserve your seat! The seats are pretty comfortable and roomier (again, at least in the main theater). They show a mix of commercial and independent films.
My #1 place to go to the movies in SF is Kabuki Cinemas in the Fillmore. You can reserve your seats (so no rush to the theater), there are great food and liquor options, and there are 21 and over theaters, so you can enjoy Toy Story without young kids in attendance (if you want to). There's a bar and bistro to hang out before/after the movie. It is pricier than other theaters ($13/ticket), so that is a drawback. To offset the higher price, I bring in my own snacks (ssshhhh). JessieR has great recommendations for seeing independent and foreign films, and I second The Castro Theater for seeing older movies, and the organ performance prior to showtime is fantastic!