Have you backed up your drive via Time Machine recently?
If not, then Time Machine is running on your local disk, making versioned copies of stuff as time goes on. This will gradually consume space-- LOTS of space. It's a wonderful feature in that it lets you recover files you accidentally delete or screw up in some fashion, even if you're away from your main backup.
That space will be reclaimed when you back up properly to an external disk drive.
There are other possibilities, such as misbehaving software causing file-system issues. Running the verify-disk function in Disk Utility will tell you if you have lost or miscounted blocks. (Fixing this, should it occur, means booting into the recovery partition and re-running Disk Utility there and telling it to repair the drive.) But usually this sort of thing is just Time Machine watching your back.
Oh, and another thing: have you emptied your trash lately? Deleting files (sending them to the trash) doesn't actually free up the space they consume until you take the second step, which is to go to the Finder menu and tell it to empty the trash.