U.S. Route 72 (US 72) is an east–west United States highway that travels for 317.811 miles (511.467 km) from southwestern Tennessee, throughout North Mississippi, North Alabama, and southeastern Tennessee. The highway's western terminus is in Memphis, Tennessee and its eastern terminus is in Chattanooga. It is the only U.S. Highway to begin and end in the same state, yet pass through other states in between. Prior to the U.S. Highway system signage being posted in 1926, the entire route was part of the Lee Highway.

The Memphis and Charleston Railroad, completed in 1857, was the first railroad in the United States to link the Atlantic Ocean with the Mississippi River. Chartered in 1846, the 311 miles (501 km) 5 ft gauge railroad ran from Memphis, Tennessee to Stevenson, Alabama through the towns of Corinth, Mississippi and Huntsville, Alabama. The portion between Memphis and LaGrange, Tennessee was originally to be part of the LaGrange and Memphis Railroad, chartered in 1838. From Stevenson, the road was connected to Chattanooga, Tennessee via the Nashville and Chattanooga Railroad. In Alabama, the railroad followed the route of the Tuscumbia, Courtland and Decatur Railroad between Tuscumbia and Decatur, the first railroad to be built west of the Appalachian Mountains.