Check your trunk
Get rid of everything you won't need on your trip. Check the trunk light, the spare tire, and don't bury the emergency kit. Leave the emergency kit til the last, and put in an accessible corner.
Pack 'getting-there' items separately
This would be everything from the 'during the trip' list. This way you won't have to unpack everything at every stop.
Pack from back to front
Put the bags you'll need at your destination at the rear of the trunk, or under other bags. Put the 'getting-there' bags - travel clothes, medications, etc. - in last, where you can easily reach them.
Last in, first out
Your 'getting-there' bags, cooler, games, etc.
Plan for spills and quick changes
Have moist towellettes, tissue, and old t-shirts (handy for spills).
Pack a small cooler
A small cooler filled with treats for children and adults will reduce costs and help make car travel fun.
Use mesh or large zip-lock bags
Good for wet swimsuits and towels. Mesh bags are also a good way to separate dirty laundry from clean.
Take an empty coffee can for fragile items
Shells from the beach, delicate souvenirs whatever you'll want to bring back in one piece.
Spare yourself agony, cost, and delay. Make sure at least one of the passengers has an extra set of car keys.