As far as actual house rules go, the biggie is going to be no divine power source, just martial and arcane. The fact that this is easily doable is is actually one of the things that excites me most about the new edition. No more clerics!
Arcane magic will be present, and quite common in some places (not Eberron level magic-as-tech common, but most good sized villages will have a hedge wizard or wise woman). In the main center of the campaign, however, magic has been very rare for the past millenia. It's coming back (casters aren't gimped or anything) but there is no magical tradition, so full casting classes are rare (if you want to play a wizard, you've got to be an immigrant, the best natives of the area can do is multiclass).
I think I'm going to go almost no magic items. There still will be magic swords and the like, but they will be very rare, very powerful artifacts that only show up in the epic tier (maybe the paragon tier). Probably no more than one per person. I'll probably introduce some sort of quality system for mundane gear, but the bonuses involved will be smaller and there won't be any flashy powers associated with them.
The other big change will be to races. No elves, no dwarves, no hobbits! No orcs, no goblins, no kobolds! The only humanoid species is going to be humans. Instead I'm going to use racial features to represent different nations (and for the main nation, social castes). The differences will be smaller than between the races as written (everybody gets the human skill, power and feat benefits, for instance) but there will be skill modifiers, racial feats that synergize with certain classes, etc.
On the opposing side, there will be very few intelligent monsters at all, other than human derived ones (lycanthropes, undead, etc.). In addition to PC races, this is obviously going to also limit opponents pretty heavily (animals, magical beasts, werewolves, undead, and humans). However, the exception based, modular approach of 4e will probably make it possible to plunder abilities from the MM races and use them for NPCs (give shifty Kobold powers to a group of bandits, or orc powers to a barbarian tribe).
So mostly rules adaption to fit the setting, rather than changing the game because I want something different. I'm really looking forward to 4e because seems like it will make it a lot easier to make some of these setting related changes than 3e did (particularly when it comes to clerics and magic items).