http://www.sheldoncomics.com/ - this is the most mainstream comic that I read - I find it really smart and clever
Comics that are on lots of people's favorites list but I can't seem to get into
Live journal comics: These are people's personal journals so not all postings will be comics. But they all do quite nice ones. A lot of journal comics (obviously) They have created a little livejournal community of web comics. Lots of comment-postings between them (and a few others I don't read). I am a lurker.
These two don't update anymore but are good enough to skip around their archive.