In the U.S. state of Virginia, U.S. Route 220 (US 220) is a major north-south state highway that extends from the North Carolina state line through Roanoke to the West Virginia state line. South of Roanoke, US 220 is a four-lane highway within the proposed Interstate 73 (I-73) corridor. US 220 narrows to two lanes north of Roanoke, connecting to I-64 near Clifton Forge and then paralleling the Appalachian Mountains north-northeasterly in the direction of Cumberland, Maryland.

Interstate 64 (I-64) in the US state of Virginia runs east–west through the middle of the state from West Virginia to the Hampton Roads region, for a total of 299 miles (481 km). From the West Virginia state line to Chesapeake, it passes through the major cities of Lexington, Staunton, Charlottesville, the state capital of Richmond, Newport News, Hampton, and Norfolk. It is notable for crossing the mouth of the harbor of Hampton Roads on the Hampton Roads Bridge–Tunnel (HRBT), the first bridge–tunnel to incorporate artificial islands, concurrent with U.S. Route 60 (US 60). Also noteworthy is a section through Rockfish Gap, a wind gap in the Blue Ridge Mountains, which was equipped with an innovative system of airport-style runway lighting embedded into the pavement to aid motorists during periods of poor visibility due to fog or other conditions.