I drove from Cleveland.
#1 BEST TIP: Join
AAA. Get a TripTik. Even if you think you won't need it.
Make enough stops to pee. Don't try to hold it until the next one.
If the sign says "Fog Ahead", believe it. Even if it is a sunny and perfectly clear day.
Bring Windex. The stuff at the gas stations doesn't always do the trick.
Stretch and do jumping jacks when you get out of the car.
If you're allergic to animals, check with the hotel to see if it is "pet-friendly." If it is, don't stay there. Even if they tell you that they do have non-pet rooms. At some point, there will have been a pet in that room and you'll react. Plus, "Pet-friendly" hotels have big dogs barking when you're trying to sleep and if you call down they'll tell you that they can't do anything about it.
Do "the wave" each time you cross a state line. Silly, but fun.
Get to the Florida Welcome Center BEFORE it closes. I was unaware that it closed and was very disappointed. (On the way home, we turned around to get back to it.)
If you aren't using a Garmin and are going through Jacksonville, pay attention to what you're doing. It is easy to get lost.
If the car doesn't have an iPod jack, make a bunch of CDs. It is such a pain trying to find the right frequency while traveling.
If you're bringing a candle to burn in the room because you're worried it might smell funky, be sure to hang on to the cap or toss the thing when you leave. Wax melts in hot cars and spills all over the seat and it is very, very difficult to get out of the cloth.

(Or maybe you're super-smart already knew that.

)
Remember that the trip home will be a LOT less fun than the trip there. Save the extra-fun car stuff for that.