As in all of the UK, driving is on the left but doable with some concentration. It helps to have a passenger gauging the edge of the road on the left side because you might overcorrect in your efforts to STAY LEFT.
An important aspect to driving in Wales is many/most of the roads other than the motorways are probably going to be narrower than what you're used to and there are going to be a lot of curves. The good news is that the condition of these roads is pretty good with few potholes or abrupt edges unlike in Scotland.
When you rent a car I'd get something smaller than what you'd normally drive yet can still be comfortable in for a couple hours of driving. Sometimes the distance between passing vehicles seems to be only 12-18 inches and a smaller vehicle offers a few more inches of comfort.
Some rural roads are either all one lane or narrow down to one lane due to constrictions like a stone wall or a hedge. There are turnouts or laybys ie wider places where a vehicle can pull off to let oncoming traffic pass. When you're on such a road it's important to notice where these wide spots are as you pass them because someone is going to have to pull over possibly requiring backing up. If you come upon an advancing farm tractor carrying a load of hay, you're going to be the one. Don't use these wide spots as a convenient place to park.
Distances may seem shorter than you're used to but don't be fooled by the 60 mph showing on your GPS, for planning purposes you're probably only going to be going 45 safely. Be aware of 20 mph flashing signs as you enter a town or village.
Roundabouts/traffic circles have become more common in NA but they are everywhere in Wales. Be very certain there's no traffic approaching from the right before you enter. Signal your intentions when leaving the circle and make sure you don't cut someone off as you exit because some the larger circles have 2 lanes exiting. And then there are the economy roundabouts in rural areas that are just white circles painted in the middle of the intersection.
Cycling is popular in Wales, give cyclists at least 4-5 feet clearance when passing. Sometimes it's not possible to pass cyclists immediately, so wait until a safe opportunity arises and don't worry about the line of cars stacking up behind you. Of equal importance are pedestrians on the road when there are no sidewalks. It's possible you might also encounter livestock.
We found the Automobile Association of GB (http://http.theaa.com) map of Wales (#6) a good companion reference to GPS and it's available on Amazon. The map road symbols give a helpful idea how wide road width is which GPS doesn't. There's an extensive network of roads in Wales and sometimes GPS suggested the shortest distance was preferable on a narrow road whereas we opted to stay on the wider roads.
Wales is a beautiful country and well worth the challenges of new driving experiences.
FYI, we took about 2 weeks circling Wales from Tintern in the south to Conwy in the north and back along the west side to St Davids. There are plenty of castles, walking paths, and assorted nature/wildlife reserves.
http://http.visitwales.com is an excellent source of indepth information that guidebooks couldn't possibly cover.
We paid for GPS with the rental and it was worth it. Fuel is sold by the liter while road distances are posted as miles.