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.

U.S. Route 21 or U.S. Highway 21 (US 21) is a major north–south United States Numbered Highway in the Southeastern United States that extends 394 miles (634 km). The southern terminus is in Hunting Island State Park, South Carolina, 14.4 miles (23.2 km) south of the junction with US 21 Business and South Carolina Highway 802 (SC 802) in Beaufort. The northern terminus is in Wytheville, Virginia, at an interchange with Interstate 81 (I-81) and US 52. Despite the "1" indicating that it is a major north–south highway, US 21 only travels through three states and is no longer a cross-country route as it has been replaced with I-77 in both Ohio and West Virginia. It also has the second-shortest length of all of the major north–south routes, just behind US 91. The route travels through the states of South Carolina, North Carolina, and Virginia. It also connects through major Southeastern cities such as Columbia, South Carolina, and Charlotte, North Carolina. The northern portion of the road travels parallel to I-77 in northern South Carolina and North Carolina. The road also has three interchanges with I-26 in Lexington and Calhoun counties in South Carolina.