Plan ahead when you can.
This probably goes without saying, but the more hotel, restaurant, and activity reservations you can make ahead of time, the better. The less you have to think about on the road, the more you can enjoy the trip.
Knowing which towns have restaurant options along the way is probably good. Trying desperately to stave off hunger until you get to the Waffle House your old roommate manages off of exit 237 is probably more stress than it's worth. Be prepared, but stay flexible.
Drive at night.
Taking off super early in the morning or driving late at night can help immensely in the realm of peace and quiet. If you're lucky enough to be a night owl and your kids are young enough to stay asleep, this can be a great way to make the drive go smoothly.
Take care of yourself.
Taking care of kids is a full-time job, and taking care of cramped kids is even harder. But, remember to also take care of yourself, especially if you're the one driving. Stop when you need to, and do whatever it takes to keep you alert and focused on the road.
Your little ones probably have appropriately-small attention spans. In an age where mobile devices dominate, there's no reason not to bring a tablet along for the sake of games and movies.
But don't rely on them alone.
It doesn't hurt to foster creativity and curiosity over pure entertainment. Kids left to their own devices can come up with some beautiful stuff! Make sure they get a chance to. Give them collaborative projects, write a song with them, and make some great memories.
Bring active toys, too.
Bring along jump ropes, beach balls, and other things that encourage activity. They can help your kids burn off some of that excess energy during quick stops for gas or food. If they can tire themselves out a little outside of the car, they may be less squirmy inside of it.
Give the kids a job.
Before they can ask "are we there yet," hand them a map and let them play navigator, or task them with squeegeeing the windows at the gas station. Find ways to get them involved, and they’ll feel like part of the team.
Think of stories to tell.
Brainstorm stories from family history that you might want to share. Your kids may be a little young to pay attention to genealogy, but they can still be entertained by hearing about their great-grandfather in WWII or about the great-great aunt who got a tattoo back in the 30s.
Plan around your children's interests.
If you have to stop for the night, it might as well be in a town where there's a dinosaur exhibit for your daughter who loves dinosaurs, right? It'll take a little more effort up front, but it'll make the trip itself more fun and a whole lot smoother.
Treat the kids.
Yes, you’re going on a vacation. However, most kids don’t really know how to sludge through the bad to get to the good. Plus, being cramped in a car for hours or days is just exhausting, mentally and physically. So, take time for little indulgences along the way.
Make packing lists.
Trying to keep track of the spouse, children, and pets is convoluted enough. Trying to keep track of clothing, toothpaste, and toys is just impossible. If you make a list for each member of the family, you're going to have a much easier time.
Put a parent in the back.
Consider having one of the adults sit in the backseat. You'll miss the company, but the kids probably need it more than you do. Plus, it’s a great way to stifle any arguments that may ensue without having to stop the car.
Bring the right kind of snacks.
Bring plenty of food for the trip, and try and be conscious of what's healthy and what's easy to clean up. Consider using a large cookie pan as a snack tray. Its large size and raised edges can help diminish spillage.
Consider alternative packing.
If you're going on a long trip and have to spend nights in different places, consider packing by "night" or "location" instead of by person. If everyone's clothes for the first couple of nights are in one suitcase, then that's the only bag you have to bring into the first hotel.