My sister (~20 trips) and mother have found driving in the UK somewhat easier as they are left-handed. As a rightie, I've logged many miles on the left (5 trips) but echo all the advice above. Never used a GPS but it sounds like a wonderful idea, only caution is some stories I've read about lorry drivers being directed into streets where their truck wouldn't fit! So GPS + common sense seems the way to go. The Michelin map book (Amazon link below) is the best printed map we've found, and would be worthwhile for the big picture even if you have GPS for the turn-by-turn detail.

Michelin map book on Amazon

If you have any doubts about your US car insurance and/or credit card company's insurance coverage of the rental, there are some alternatives to the criminally high cost of insurance from the rental company itself. AmEx has a "premium" package you can purchase, and there are some other third-party companies that offer coverage.

Make sure your U.S. passport is good for at least 6 months AFTER your return from UK, otherwise they won't let you in! There are other great tips at a site called Slow Travel. Although it is aimed at those taking longer trips, and covers all of Europe, you will still find great info on the site and forum.

Have fun and show us lots of pics when you get back!