State Highway 21 runs from the Texas-Louisiana boundary east of San Augustine to San Marcos in east and central Texas. SH 21 mostly follows the alignment of the Old San Antonio Road and the El Camino Real, except for the portion between Midway and Bryan, where the Old San Antonio Road took a more northerly route, and SH 21 follows a more direct route. That section of the Old San Antonio Road is served by Texas State Highway OSR.

Midway is a city in Madison County, Texas, United States at the junction of the La Bahía Road and the Old San Antonio Road in northeastern Madison County.