Most of what I could say is covered above, with a couple exceptions that may or may not apply to your specific case:
If you use Adobe Bridge, the cache folder can get quite amazingly big. I cleaned mine out the other day and ended up removing 8gb of extra space. Also I'm using CS4, and I noticed that my CS3 cache folder was still around even though I got rid of CS3 a while ago. Another 2+ gigs there.
I also use Parallels 4 and it has a nasty tendency to use up all of the free space given enough time, but a computer reboot handles that. This could be just me though. If you do have Parallels or Fusion and have regular snapshots made, that could also be a factor.
I use Whatsize to check what's taking up space, but I got my copy before they started charging. I like it better than the other ones I've seen.