i'd rather Nintendo choose a more standard button layout for their next system. i LOVE the idea of the A button being larger. Ideally, it would be mapped to the function that would be performed the most (aside from moving), but as Ian Sane said, for third parties this isn't as ideal. A pad more like his, with equal emphasis on the "action" buttons is what i'm looking for. A bigger D-pad wouldn't hurt. My medium thumbs have no problems with it but i could see how many people would.
i also like ThePerm's idea of two buttons on the back, similar to the N64's Z button. It keeps the face of the controller less cluttered, and gives the player two more options. A "select" buttons, they'd be great for picking weapons (hold one down and scroll through weapons with the analog stick). The main problem is that no one expects buttons on the back of the controller. Most people who first grab the GC controller don't even noticed the Z button. If it's not on the face, it won't get used. Scratch that idea.