Another cool thing to do is to follow a famous route, e.g. the Oregon Trail which runs from Independence, MO, to Oregon City, OR. Use a good guidebook like The Oregon Trail Revisited by Gregory M. Franzwa. (Or click here.) I did this once. (Actually, I did different parts of it on different trips.) A wonderful experience.

There are also guidebooks for
the route of Lewis & Clark,
the Santa Fe Trail,
the Mormon Trail,
the California Trail,
the Lincoln Highway (plotted in 1913 from New York City to San Francisco),
Route 66 (Chicago to Los Angeles),
the Great River Road (follows the Mississippi from Minnesota to Louisiana, and includes some connecting roads in Ontario) (also click here)

Those are all the important routes I can think of right now, but I'm sure there are more.