Apps & Widgets
Haven't used AIM since Facebook and Skype came into your life? Drop it. Don't need that desktop widget telling you the temperature outside? Get rid of it for good. Do it yourself or use software like AppCleaner (for Mac) or Revo Uninstaller (for PC).
You don't want to delete any of the fonts that came pre-installed with your machine (they're probably used by your system in some fashion). But if you've added any addition fonts over the years, purge the unused ones. Believe it or not, fonts can eat up valuable hard drive space.
By thinning out the pictures you have stored on your hard drive, you'll free up tons of space. Back up the ones you want to keep, then dump everything else. Do it manually by sifting through your library, or use software designed for your machine. A Mac friend of ours swears by Duplicate Annihilator, a program that automatically thins out your iPhoto library by hunting and killing duplicate photos.
Do you speak English? Type in English? Read in English? Then there's really no need to keep a bevy of foreign languages installed for your system. Do it manually (here's a guide for Windows PC users), or find a program to do it for you (Like freeware Monolingual for Mac).