I've done it for several long-distance hauls. Just drive carefully and cautiously (a good idea regardless of a bike mount). Check with your home/auto insurance about coverage if you have an accident or theft.
The more tightly you can cinch the bikes to the rack, the better - I always use several bungee cords and some tie-down straps for extra piece of mind. Basically, if you try to shake the bikes, the car should be moving as well. Detach any accessories that might fly off (lights, saddle bag, water bottle, etc). Tie a red flag or other obvious marker to the bikes for extra visibility. People should be giving you extra space if they see the bikes, but just in case.
Lastly, I recommend locking everything together with U-locks or good cable locks so that you don't have to worry someone will steal your bikes if you take a quick trip inside rest stops. If you stay at any hotels along the way, bring your bikes inside with you. Some places are weird about this so my typical plan is to check in without mentioning it, then pull my bike inside through a side door or other entrance to get it into my room.