Map of US highway 21 and family

US 21 is represented by the purple line beginning at Hunting Island SC. Its current northern terminus is in Wytheville VA; the red line north of there to Cleveland is the historic extent of US 21.

US 121 is the green line from Beckley WV to Pound VA. Though it does connect with the route of historic US 21, it was commissioned some 30 years after US 21 ceased to exist in Beckley, so it wasn't the most appropriate number that could've been assigned. US x19 and US x23 would've been better (click to view maps of US 121 in the context of those route families).

US 121 (historic) is the red line beginning in Lexington NC. It went north to at least Ft. Chiswell VA, but probably would've been co-signed along the dashed line to end in Wytheville.

US 221 is the blue line from Lynchburg VA to Perry FL.

US 321 is the blue line from Lenoir City TN to Hardeeville SC. Its signed direction reverses in Elizabethton TN.

US 421 is the blue line from Michigan City IN to Ft. Fisher NC. For a time it followed the red line in far western Virginia to Cumberland Gap.

US 521 is the blue line from Charlotte NC to Georgetown SC.