So how do we do it? Well, here is a list of a few things that make these trips smooth. I would caution that some of these we learned the hard way and won't work for everyone else.
1. Lists, lists, lists! At least a few days ahead of time I make a HUGE list of what all needs to be taken on the trip. This includes food to prepare meals we will make there, personal items for each family member (be sure to remember any special items your kids can't do without), and a to-do list to complete before the trip.
2. Decide on your optimal travel time. For us this means leaving at night. We dress the kids for bed and load them in the car about bedtime. This usually ensures they are asleep within an hour and don't get too fussy. It does NOT mean that they sleep the entire way there, though usually any waking results in falling back to sleep relatively quickly.
3. Pack in a way that will make sense when you get there. For us, this means I pack all my toddlers items in one bag as he sleeps in his own room, and the babies things get put in mommy and daddy's bag (or his own if there isn't room). All the food usually gets packed together or with any other misc items. We also pack a "snack bag" that stays up near the front seats.
4. Remember to have fun in the midst of spilled drinks, fussy babies, and multiple stops, you can't control everything. Just try to move on and know that if you can't laugh about it now....you'll be able to one day :)