Be careful taking Julia's advice ("Get the smallest car you can use"). In the UK a small car is very small indeed. My wife made the arrangements for the car rental on our last trip. She explained she needed a car that could handle three people. The car they held for us (a tiny little 2 door Volvo I think) could hold three people, but there was no room left for luggage. We ended up in a 4 door Ford Mondeo.

The suggestion that you get a car with an automatic transmission is a good one. The tiny little car had it, but it was literally the only car in the lot with an auto trans. Such vehicles are apparently not common in the U.K. When we moved to a larger vehicle we lost the auto trans. However, the standard trans on the "wrong" side did not prove to be an issue.

Be prepared for major sticker shock when you purchase gas. No matter how outrageous you think the prices you are currently paying in the states, in the UK they will look like a bargain.

Buy a good road atlas. Or several.

The signage was generally good but we did have the occasional problem The worst/funniest was outside Newcastle trying to figure out which ramp to take. We could see on the map what we wanted to do, but the options offered by the signs didn't seem to match the map. We circled Newcastle and cruised by the Newcastle Brown Ale plant three times before we finally made the right choice.