The major north-south highways are U.S. 195 in Washington and U.S. 95 in Idaho. These highways provide access for the Clarkston-Lewiston, Pullman-Moscow and Colfax areas to Interstate 90 in Spokane. Traveling east, U.S. 12 connects to U.S. 195 and U.S. 95, and traveling west of the District, connects to major highways I-84 and U.S. 395.

Additionally, State Route 26 runs west from Colfax and connects with U.S. 395, and on to Interstate 90 at Vantage. This is a major route west to Seattle. State Highway 129 is the major north-south highway between Clarkston and Enterprise, Oregon.