The less I have to use the mouse the better. It only serves to slow me down. I've memorized hundreds of shortcuts in the programs I use regularly, but with the release of Vista, I have a slew of new shortcuts to play with. Here are a few of my favorites:

WinKey + number Starts a program from your quick launch tray. e.g. WindowsKey + 1 starts the first item in the quick launch tray.
WinKey + SpaceBar Brings the side bar to the front
WinKey + type Program Name + Enter This opens the start menu and searches through your program shortcuts. Very rarely do I ever have to browse through the "All Programs" link. I just start typing the name of the program I want and hit enter when it shows up.

Check out the Shell team's blog for even more shortcuts.