Yesterday I spent two hours with the core books at a friend's place.
The rules are completely different, but the game’s philosophy goes back to AD&D1. The “role playing” part of the game is downgraded compared to 3E, and everything is around combat, combat and more combat (the famous “character roles” are exclusively defined by it). The “noncombat encounters” chapter in the DMG gets only 17 pages and includes puzzles and traps.
Even the artwork is different compared to 3E. Everything is grandiloquent, over-the-top. All depicted characters are fighting or with their weapons (or powers) ready. No one is smiling, relaxed.
Because of the game’s philosophy, I can’t imagine many D&D3 campaign settings being played with D&D4. Again, it’s too combat oriented. For example, it would be very difficult to play Freeport or Midnight with it.