Drug them PROFUSELY!
Just kidding. I have only had to give my kids meds on very few occasions when I have traveled. Mostly it has been allergy related. I find giving them "yucky" types of medications only increase the tendency for them to throw up and well... that is just nasty when it happens on the first day and you have three more days to go. (This is the voice of experience speaking).
I have found that listening to audio books is a great way to pass the time for all involved. We have never had any of those fancy smancy DVD players in our cars. They are just to new a concept for our old cars. So we listen to stories. Lots of stories.
Next I make them (meaning the kids not the aliens) a snack bag of food. This bag pulls double duty. It starts out as a snack bag but then becomes ... wait for it ... a trash bag! I use those gallon ziplock bags that I then fill will all sorts of food. As they eat there trash goes in the bag then I just have to fish out four bags of trash instead of a gazillion pieces of nastiness. That is the bag they get for the day. If they go through all of their snack before 10am, well they have to wait until the next day for their next bag. They have gotten pretty good at making their snacks last.
Remember that CapriSun Juices make great ice. I have found that filling a cooler with ice just makes a mess as it melts. Stuff get soggy, mushy, and just plain gross. So I went to freezing two boxes of those CapriSun's and using them as ice. It keeps everything cold and as they melt they just become ready to drink. Works slick, avoids a lot of mess, and makes for some yummy slush type drinks.
Always start with a clean car. By the time you finish traveling your car is going to look like it got bombed. Don't start with it that way or you will be shoveling out crap-o-la that does not have any definable origin and is probably radio active.
If at all possible, drive at night. When the kids sleep, mom's can breath a sigh that all is quiet on the western front. I know lots of you out their aren't night drivers, but if you are it is better. They go to sleep, you drive, they wake up, your there. You avoid all of the "are we there yet?" whining that accompanies all travel.
Be prepared to stop. Kids have to pee often. and stretch often. and generally need a break. So let them have one and just know that your schedule is just flexible.
But mostly, and I mean the biggest part of having a good trip, is to have a sense of humor and a good attitude. If you think it is going to be hard and horrible then it will be. Your kids will be themselves in or out of the car. If you have prepared, then you just go with it. If they scream, turn on your music to punk rock and scream to a beat. If they whine, take a deep breath and whine back. Things happen. Like throw-up and pop tart goo and sibling beatings but all of that can be dealt with if you just breath and smile and not take yourself or your kids to seriously.
A little prayer never hurt either.