U.S. Route 21 in the context of "United States Numbered Highway System"

The United States Numbered Highway System (often called U.S. Routes or U.S. Highways) is an integrated network of roads and highways numbered within a nationwide grid in the contiguous United States. As the designation and numbering of these highways were coordinated among the states, they are sometimes called Federal Highways, but the roadways were built and have always been maintained by state or local governments since their initial designation in 1926.

The route numbers and locations are coordinated by the American Association of State Highway and Transportation Officials (AASHTO). The only federal involvement in AASHTO is a nonvoting seat for the United States Department of Transportation. Generally, most north-to-south highways are odd-numbered, with the lowest numbers in the east and the highest in the west, while east-to-west highways are typically even-numbered, with the lowest numbers in the north, and the highest in the south, though the grid guidelines are not rigidly followed, and many exceptions exist. Major north–south routes generally have numbers ending in "1", while major east–west routes usually have numbers ending in "0". Three-digit numbered highways are generally spur routes of parent highways; for example, U.S. Route 421 (US 421) is a spur off US 21. Some divided routes, such as US 19E/US 19W and US 25E/US 25W, exist to provide two alignments for one route. Special routes, which can be labeled as alternate, bypass or business, depending on the intended use, provide a parallel routing to the mainline U.S. Highway—an example being US 74 and its many special routes.

U.S. Route 421 (also U.S. Highway 421, US 421) is a diagonal northwest–southeast United States Numbered Highway in the states of North Carolina, Tennessee, Virginia, Kentucky, and Indiana. The highway runs for 941 miles (1,514 km) from Fort Fisher, North Carolina, to US 20 in Michigan City, Indiana. Along its routing, US 421 serves several cities including Wilmington, North Carolina; Greensboro, North Carolina; Bristol, Tennessee and Virginia; Lexington, Kentucky; and Indianapolis, Indiana. US 421 is a spur route of US 21, which it meets west of Yadkinville, North Carolina.