I'm concerned about some of the large flavor/fluff changes that seem to be happening. I'm all for mechanic streamlining and simplification, but I'm afraid that flavor changes that are incompatible with my campaign (the changes to demons/devils, and the revised cosmology) will be deeply enough integrated into the new rules as to make it a major pain to updated my campaign to 4e.
Similarly, I'm worried about the whole wizard schools flavor, etc. In fact, I'm just overall worried about the implied flavor of the core rules, none of which I have liked thus far.