U.S. Route 321 (US 321) is a spur of U.S. Route 21. It runs for 516.9 miles (831.9 km) from Hardeeville, South Carolina to Lenoir City, Tennessee; with both serving as southern termini. It reaches its northernmost point at Elizabethton, Tennessee, just northeast of Johnson City. Because of its unusual "north–south–north" routing, U.S. Route 321 intersects both Interstate 40 and U.S. Route 70 three separate times. The highway serves different roles in each state: An alternate route to interstates in South Carolina, a major highway in North Carolina, and a scenic route in Tennessee.

Interstate 40 (I-40) is a part of the Interstate Highway System that travels 2,556.61 miles (4,114.46 km) from Barstow, California, to Wilmington, North Carolina. In North Carolina, I-40 travels 420.21 miles (676.26 km) across the entirety of the state from the Tennessee state line along the Pigeon River Gorge to U.S. Highway 117 (US 117) and North Carolina Highway 132 (NC 132) in Wilmington. I-40 is the longest Interstate Highway in North Carolina and is the only Interstate to completely span the state from west to east.