First thing is first, when you are driving anywhere that is farther than 2 hours away expect to make several stops. I tend to tack on about 15 minutes per hour of driving; so a 4 hour drive will probably be a 5 hour trip. (depending on time of day)
Tip number 1: Accept this fact, embrace it, and move on. My first trip down to TX was brutal and frustrating and long all because I let it bug me that I couldn't drive more than an hour and a half or two without stopping... on that note, no offense La Leche League but breastfeeding seriously sucks sometimes.
I have a two year old and a 3 month old so I wasn't concerned about constant bathroom breaks, what was more distressing was how in the world I was going to keep my toddler entertained as well as preventing my infant from getting sick of the car seat.
Tip 2: Stop often but play it smart. I literally just followed the lead of my kids. When they slept I booked it, held my pee, let my stomach growl, and jammed out to my music; you better believe I didn't dare stop until they were awake and needed things.
Tip 3: When you do stop, make it worth it. Every time I stopped the rest was usually about 15 minutes and a few times it was longer. I ate and/or stocked up on snacks and drinks, changed the girls, and tried to get them out of the car for a while.
Tip 4: Rest areas and grocery stores are your new best friend. Almost every time I stopped it was at a Wal-Mart or rest area. Seriously. The snacks/food and anything else you need will always be cheaper than a gas station, cleaner bathrooms with guaranteed diaper changers, and it's the perfect place to let the kids stretch their legs because they're big and grocery stores have those silly .25 cent rides. *Plus, lots of Wal-Marts have CHEAPER gas.
---In terms of Lela, my 3 month old, I would wear her in my Ergo carrier. I literally walked around feeding her while letting Ava play. There was a few times she came unlatched and her sucking attempts to re-latch caught a few peoples attention but whatevs---
Tip 5: Invest in a portable DVD player and a plethora of long DVD's. It would be WAY too easy if the kids slept the whole entire trip, but they didn't and that DVD player seriously took off some of the pressure to entertain.

Tip 7: Know your surroundings. Before I went on my trip I took a glance at what towns or cities I was going to be going through and whether or not they had stores, tourist stuff, or whatever! The first time I underestimated how little there really is in OK and TX which is how we ended up half an hour away from our destination and camped out in front of Target waiting for my sister to meet us.

Over all I had a blast. It was my first long trip alone with two kids and the trip back home went more smoothly. I was exhausted and wobble legged when I got home but now I have this sort of "I'm a badass let's drive to Alaska just because" sort of feeling.
We do have a flight overseas in a couple months. Bring it on.