This is my setup that I use after experimenting with quite a few layouts.

01-10 keys are your first 10 buttons on your action bar.
11 - (F) Assist key
12 - (Alt-F1) Pet Attack
13 - (-) Button 11 on your action bar
14 - (Ctrl-; ) Autorun
The second mouse wheel I use as the F2 and F3 key depending on whether I roll it up or down. If I roll it down (toward me) all the alts follow the toon on the screen I'm on. If I roll it up, I set it for instant damage. For example, on my locks, if I spec for it, I'll set that to Shadowburn. If I was playing mages I might set that to an instant damage such as fire blast.
The Direction pad is set so I can steer my character. Being able to do this with my thumb is very useful for strafing and letting me select things with my mouse.
The space key is set for jump.
The F12 key is to have all my characters mount up. In the past, I have also used that as my Ventrilo button and that worked well also.
I use keyclone, and using this and the mouse makes it very easy to set up a 'white-list' and only pass through the buttons I use.
Hope this helps!