The car ride:
First of all I think everyone with kids should have a car vacuum, vacation or no vacation. They are small and they plug into your cigarette lighter. On a vacation where you are in the car a lot it's so nice to be able to get rid of all the crumbs from snacks.
Pack lots of snacks. If you are taking fruit cut it up and put small portions in small zip lock bags. We put all of our cold food in a insulated grocery bag with some frozen water and it worked really well. Make everything able to just be able to grabbed and passed out. Take plenty of wipes for cleaning up the snacks.
If your budget will allow buy some new toys and books and put away until the day of the trip. If you can't do that put some toys away about a month before the trip so that they have a newness about them. You can grab books your child has never seen at the library. Pick interactive books, like the simply look and find books, books with flaps, turny wheels, fold out pages, etc. I would recommend "Curious George Discovery Day" my daughter loves any of the Curious George board books (the board books not the regular books) and "Pat the Bunny Hide and Seek." Also sticker books are super good. I bought some at the dollar store and also bought a vinyl sticker book that worked well.
We bought a car seat tray because there were rave reviews about them. M* wouldn't have anything to do with it and we got along fine without her using it. So I would say save your money.
Break up the drive. Plan on stopping about every 3 hours. We even broke it up bigger by stopping halfway and staying the night.
If you have you or your partner go upstairs to the room before your kid and childproof what you can. For example we were in our room for 5 minutes and M* broke one of the coffee mugs they put out, almost crushed herself with a table lap and called china with the phone (alright maybe a little exaggeration but not much of one).
Bring the toys in from the car. Subconsciously I thought we would just relax in the hotel room but reality said, "Hello! Have you met your daughter? She doesn't know how to relax." So take something to entertain in the hotel room.
If possible take a pack and play. Especially if you plan on staying in more than one hotel. Having a little consistency in where they sleep will be a big help. Not to mention that hotel cribs look like something out of a horror film.
You know your toddler best, if they aren't the type to wait patiently for something don't plan on going somewhere where they are going to have to wait a lot unless you are willing to deal with the tantrums that ensue.
We bought a harness backpack. This is one thing that I saw before I was a mom and scoffed at but M* is a runner so we bought one. People pointed and laughed a little at it but I say it's worth the peace of mind.I had trouble deciding whether to take our big stroller that folds down so M* could take better naps and our cheap umbrella stroller. Due to space constraints we took the small umbrella stroller. M* only slept for 1/2 hour in it and there wasn't really ever a time I was glad I had the small stroller so I say if you can pack your nice one with the basket and fold back seat.
Speaking of nap times bring the lovey with you everywhere if it's small it'll help your little one fall asleep better.