I think too many here are focusing on what the Dems will use against him. I meant to emphasize what would his GOP opponents use. Some of the answers here are moot because the rhetoric just won't resonate with the Republican base.
Like I said earlier, I guess foreign policy is an area he could be hit on but unless he's a total disaster/delivers a whopper of a gaffe, I don't see that as a problem either.
Charisma might be a question mark but he isn't really going to be attacked on that. I guess if he's far too bland, it could be the single biggest issue.
For the GOP primary, they will probably test the limits of his debating composure, betting that he has less speaking finesse than his lawyer/preacher opponents. If he rises to the top of the pile, they will try to quickly bait him into a Rick Perry or Sarah Palin moment.