Interstate 66 (I-66) is a 76.32 mile east–west Interstate Highway in the eastern United States. The highway runs from an interchange with I-81 near Middletown, Virginia, on its western end to an interchange with U.S. Route 29 (US 29) in Washington, D.C., at the eastern terminus. Much of the route parallels US 29 or State Route 55 (SR 55) in Virginia. I-66 has no physical or historical connection to US 66, which was located in a different region of the United States.

Interstate 81 (I-81) is an 855.02-mile-long (1,376.02 km) Interstate Highway. In the US state of Virginia, I-81 runs for 324.92 miles (522.91 km), making the portion in Virginia longer than any other state's portion of the route. It is also the longest Interstate Highway within the borders of Virginia. It stretches from the Tennessee state line near Bristol to the West Virginia state line near Winchester. It enters Virginia from Bristol, Tennessee, and leaves Virginia into Berkeley County, West Virginia. The route passes through the cities of Bristol, Roanoke, Lexington, Staunton, and Harrisonburg.