Whether you'll be driving for several hours or even into the night, be sure to wear comfortable clothes and shoes. Experienced travelers will tell you that a road trip is not the time to wear your tightest jeans, or anything that restricts or binds.
You'll also find that shoes that are easy to take on and off are a practical choice. That way, you can wiggle your feet in the car and then slip your footwear back on at moment's notice when you stop for a break. Add a sweater or jacket over a T-shirt for instant respectability in public areas.
If you're traveling with a companion, a small blanket works wonders to help keep you comfortable if the two of you disagree on the temperature setting. And a pillow from home can provide just the comfort you need in an unfamiliar hotel bed.