I do it all the time. But I avoid driving into big cities - horrible rush hour traffic, hard to find parking, some sections of cities are off-limits to cars of non-residents earning the unaware big fines. Plus gas is $8 a gallon and highways are all toll roads. Parking in cities can be expensive.

Some rules- on highways, left lanes are for passing - you will annoy other drivers if you hang out there too long. Drivers are aggressive and will dart in and out - if you leave a car length between you and the guy in front, someone else will occupy it. In towns, cars from side streets will just out and force you to stop so they can turn onto your road. You really have to be aware at all times when in traffic. When a traffic light turns green, people start honking to get traffic moving - don't take it personally.

If the trip is mostly from big city to big city, I'd highly recommend taking the high speed trains (saving time and money) and using taxis to go from stations to hotels to avoid lugging luggage (or pack light). If you're going to small cities and out of the way towns, then a car becomes much more convenient.