I would love to do a road trip in southern Wales and around to Cornwall. But, to be honest, driving on the opposite side of the road scares the heck out of me.
Manual transmissions are much more common in UK (and the rest of Europe for that matter) than in the US, so unless you're prepared to pay considerably more for your hire car to have an automatic transmission, you will be shifting with your left hand. I got used to that quickly, but your mileage may vary. You can acclimatize to driving on the left--you'll need to concentrate at first when you encounter a T intersection. That's when you're most likely to choose the wrong lane to turn into. Another aspect of driving in the UK that American drivers will be unfamiliar with is roundabouts. The video below gives a comprehensive lesson on negotiating roundabouts in the UK.
You will note in the video that sometimes cars are parked along the street, taking up most of the driving lane. This is very common, and you should be aware that cars approaching you in the opposite direction on a street where this situation exists may be partly in your lane, and that you will sometimes find it necessary to drive partly in the lane of approaching traffic.
You can look at the UK government site for more information: The Highway Code, road safety and vehicle rules
I got the Highway Code book and read it when I began driving in the UK--it's fairly helpful. You also might consider getting yourself a magnetic "provisional plate"
to attach to your the back of your hire car, which may help with people giving you some leeway on the road when you make mistakes. It's not necessary and I never used one, so I don't know if it would actually be any use. You don't strike me as somebody who would be particularly bothered by people honking at you, yelling at you and making rude gestures, so . . .
I also advise getting a GPS ("satnav" in the UK) with a western Europe map installed, which will help you avoid unnecessary driving errors. It will also help navigating through roundabouts because it will tell you which exit to take as you approach.
The learning curve for an American driving in the UK isn't terrible, and though the above may sound intimidating, it's only because I tried to think of the various things I've learned over the years. I didn't have a GPS for the first few years when I drove in the UK, and so I had plenty of adventures with wrong turns. Signs identifying streets and roads are often only a few feet off the ground, so can be blocked by undergrowth, traffic, or parked cars, which doesn't help.