We do two road trips/year to southern CA to visit the in-laws with all three kids (now 7, 5, 2) and have been doing said trip since the first one was born. We rarely have problems now, used to be a pain because we weren't ready for all the stops for babies. Be prepared to stop AT LEAST every 2 hours and look for parks and other running areas (McD with play areas are GREAT!) Plan to stop for at least 15-30 minutes at each stop.
Now, for in the car, go to dollar store and get new crayons, color books, "workbooks", spiral notebook (a la Blues Clues), a new toy (or two), stickers and (ready for this magic thing???) a metal cookie sheet. They can use the metal cookie sheet to put the stickers on (to "decorate") and to use as a lap desk for coloring. If they aren't mouthers (don't put things in their mouths), get pipecleaners. My kids LOVE to make things out of the pipe cleaners for grandma. I can't always tell what they are, but the stories for grandma are great. By the way, I also put all the toys for each kid in a giant dollar store gift bag.
If you want to spend a little more money, get the color wonder stuff (keeps the car clean). I like fruit loops for a treat, and juice boxes for drinks. I used to also bring the leap frog toys that are little. And the Story Reader that reads to the kids when turn the pages. Get your DVDs from RedBox and then return them to a RedBox when you get there. And pick up a few kid sing-a-longs (dollar tree usually has some). We also get some books on tape from our library.
It can be fun, with planning. Feel free to ask for more details anytime! Good luck! Maybe we'll see you on the road..we're going down (16 hour/2 day road trip) in June. :)