you might try looking at the fly drive deals, thats when all the complications of multi state car hire are taken care of.
Ive driven a lot in the states, across states, across half the country. If you are with a like minded person who likes long long straight roads into nowhere where you can stop off, explore, then you'll be fine. Fuel is still fairly cheap to what we are used to. If you are with someone who gets bored spending most of a week in a car.. avoid, get a flight.
If you book from here with a car company, do a voucher offer search from now to when you book, as its often the case you can make some decent savings.