The all caster game. Every player runs a cleric, wizard, psion, or similar. Likely using a very decadent, aristocratic setting, where magical ability carries serious political significance. (And perhaps there are lots of angry barbarians out to bring down the pleasure-seeking, slave-holding, demon-worshiping establishment that the PCs happen to belong to?)
The all psionics game. I like psionics, but I've never really gotten a chance to use it. There'd still be fighters and barbarians and so on, but anyone who casts spells would be out, and magic items would be completely replaced by their psionic equivalents.
Tome of Battle, Tome of Magic, and Magic of Incarnum. I have 'em. Never used 'em. 'nuff said.
Gestalt. And maybe a bunch of other house rules from Unearthed Arcana, but this is the main one. This would definitely be an opportunity to use the previous idea, and maybe even the "all caster" bit. I'd just declare that one of the two classes used has to be of that variety.
Iron Heroes. Again, got the book, never used it. I'll probably someday use it for a one-shot or something. I'd consider throwing in some Book of Nine Swords guys, for mechanical variety and possible philosophical conflict. Actually -- a whole game where "those fancy pants fire breathing guys" and "those luddites who think magic items are going to eat them or something" have to team up against a problem both of them hate (say, demon summoning sorcerers or the like) could be pretty cool, in a bad kung fu movie kind of way.
Arcana Evolved. Ran it once, had fun with it, and I'd like to do it again. I'd probably want to make up my own setting, though. And ditch Litorians. Another book I'd consider mixing ToB up with.