Pennsylvania Route 21 is a 50.75-mile (81.67 km) long east–west state highway in the US state of Pennsylvania. The western terminus of the route is at the West Virginia state line in Richhill Township, where PA 21 continues into West Virginia as West Virginia Route 891. The eastern terminus is at U.S. Route 40 Business in Uniontown. The route is known as the Roy E. Furman Highway for most of its length. PA 21 serves Waynesburg and Masontown along the way.

Uniontown is the largest city in and county seat of Fayette County, Pennsylvania, United States, 46 miles (74 km) southeast of Pittsburgh. The population was 9,984 at the 2020 census. It is part of the Pittsburgh metropolitan area.