[1] Along most of its length, Illinois 21 is called Milwaukee Avenue.

North of Gurnee, it is called Riverside Drive.

The towns of Glenview, Libertyville, and Gurnee are principally located along this road.

It follows the Des Plaines River for its entire length, and overlaps U.S. Route 45 between Lincolnshire and Prospect Heights.

South of Illinois 43, Milwaukee Avenue remains a major arterial road until it reaches the downtown area of Chicago, where its historical terminus at Lake Street has been moved back to Grand Avenue.