U.S. Highway 21 in the pre-Interstate era was a north-south highway connecting the area around Lake Erie and the coastal South. One of the few true north-south routes to cross the middle Appalachian Mountains, it became an important corridor for motor traffic between northeastern Ohio, western Pennsylvania, (with U.S. Highway 19) and western New York state and central North Carolina, central and southeastern South Carolina, and with U.S. Highway 17 from the 1930s, coastal Georgia and most of Florida
U.S. 21 originally (in 1926) connected Cleveland, Ohio and Jacksonville, Florida. During the 1940s it was truncated at Vaucluse, South Carolina as U.S. 17 was extended in its place; U.S. 21 was then diverted to a dead end through Beaufort, South Carolina to its current southern terminus at the Atlantic coast at Hunting Island State Park.
In the Interstate era much of US 21 became an obvious corridor for a long-distance expressway. The West Virginia Turnpike between Charleston, West Virginia, and Princeton, West Virginia, was the first segment of a planned series of toll highways along or near U.S. 21 from Cleveland, Ohio to Charlotte, North Carolina All of the other toll highways were shelved in favor of freeways built with Interstate funding, these freeways and the West Virginia Turnpike, became Interstate 77, which completely supplants old U.S. 21 as a long-distance through route. Interstate 77 was later extended to Columbia, South Carolina, also within a few miles of U.S. 21.
Between Cleveland and Charleston, all but a relatively short segment of U.S. 21 was completely decommissioned in favor of Interstate 77, the relics being Ohio State Highway 21. (An Ohio State Highway 821 between Cambridge, Ohio and Marietta, Ohio is "Old 21", and is strictly a local route).
Between Charleston and its current northern terminus at Wytheville, Virginia, almost all of U.S. 21 coincided with either U.S. Highway 60, U.S. Highway 19, or U.S. Highway 52, which remain as U.S. 21 was decommissioned. The short segment of U.S. 21 in southern West Virginia not coinciding with another U.S. route became an extension of West Virginia State Highway 16.
U.S. 21 has or has had several related routes: