Route 66 was a popular highway a long time ago. The road was first created in 1926. However, it got removed from the road system in 1985 due to the Interstate highway system. However, several portions of U.S. Route 66 became State Route 66, 166, 266, etc.
In Cars, Route 66 is the route that Radiator Springs is on, somewhere in western Arizona or eastern New Mexico. Back in 1965, the town was popular. However, when Interstate 40 was built, Radiator Springs and Route 66 lost it's population, and was even taken off the map.
40 years later, Lightning got lost in Radiator Springs and wrecked the road. He was sentenced to fix the road before he could leave. During his stay, he learned about the history of Radiator Springs and Route 66, and realizes that he's been missing a lot. Finally, he fixes the road, but decides to stay a little longer to buy new tires, organic fuel, night vision goggles, bumper stickers, and even a new paint job. However, his stay didn't last very long when Mack and hundreds of reporters came and took him to the tie-breaker race.
After the tie-breaker, he comes back to Radiator Springs, announcing that the town was back on the map and that he wants to live here.