We've always hired a car, the rates can vary within the same company in different parts of the US, eg Dollar is good value on the West coast but the dearest in Florida. Usually we rented through rentalcars.com who are now, I believe, a part of booking.com, we've never had problems with them and when we had a problem with the US company they were very helpful. It's essential to get cover for CDW, Collision Damage Waiver, it's much cheaper in the UK than through the companies though check what's included before you buy it. Check what's covered through your travel insurance and home insurance regarding personal property and make sure that your not bounced into ticking anything you don't know about after a long flight!
Make sure you turn off data roaming before your flight, it cost me £50+ when I forgot. You can buy a fairly cheap pay as you go from somewhere like Walmart once there.
I've always found driving in the US very easy, but we did live in Europe for a while.
Check about toll roads where you're going, some will not take cash. In Florida there are cash tolls in the main tourist areas, make sure you have lots of quarters, in other parts we bought a Mini-Sunpass from Walgreens etc for about $5, much cheaper than paying the rental company a daily rate.