Route 21 is a highway in eastern Missouri. Its northern terminus is at Route 30 in Affton. Its southern terminus is at the Arkansas state line (where it continues as Highway 115). In the St. Louis area, it is known as Tesson Ferry Road, which was named after the 19th century proprietor of the ferry across the Meramec River.

The section through northern Jefferson County, Missouri was the site of numerous fatal traffic accidents due to the narrow road being unable to handle increased traffic from "population growth", and was referred to as "Blood Alley" and "Missouri's Most Dangerous Highway" (and was featured in an Reader's Digest article on dangerous roads)[citation needed]. As a result, the road was rerouted and built to freeway standards. Construction to reroute the highway to just south of Hillsboro was completed on December 15, 2008 and Route 21 is currently freeway standard from Route 141 to Highway B. Plans to extend the freeway south to DeSoto have been approved, but funds are lacking to complete this part of the project.

Residents of the area designated as "Bloody Alley" along Route 21 believe that the vast majority of accidents along that stretch of road are due to drunk driving, inattentive driving and speeding. The road only infrequently has heavy traffic patterns that could be attributed to "population growth" and is one of the lesser travelled roads of the area according to MODoT traffic volume maps.[citation needed]

Route 21 from the Meramec River to Route B, along with Route M, make up the Jefferson County Scenic Byway.

Exits are not numbered.

Business 21 follows the old alignment of Route 21 through the city of Hillsboro. It begins at the intersection of Route 21 and Highway B on the southern edge of the city, and continues north to the intersection of Route A and Old Route 21, where it ends. Business 21 is the only way one can now reach Route BB, as the rerouting of Route 21 bypasses the road.