We drive from Oklahoma (20 hours if we did it straight through

), and have done that with DD anywhere between 26 months and 4y11m. A DVD player with headphones has been a lifesaver. Mine wasn't reading when we took our last trip, but I'd pack a stack of books for her if we were to go now.
We've tried driving at night, in hopes DD would sleep for more of it, but we've found it works better to just leave early in the morning. Our first day, we go about 14 hours, then 6 the next day, and spend the afternoon at one of the parks.
The rule of "everyone pees every time we stop, even if they don't have to go" is also one that's worked well. We drive through the "future I-22 corridor" aka 3 hours with no services, so we stop at each end and hope not to have to stop in the middle.
We started out with 4 people in a minivan, but it really isn't any more crowded with 4 people in a Camry, and the mileage is so much better.
I've flown that trip before, and I personally prefer driving. Flying for us takes an entire day and can be a hassle with kids.