Interstate 55, a major north-south national corridor, runs through the region through Ste. Genevieve County and offers direct access not only to the St. Louis metro area, but also brings the majority of the nation within a one-day drive. Additionally, while not an Interstate, U.S. 67 is a divided four-lane freeway that runs through St. Francois and Madison Parkland REDI counties, intersecting with I-55 just to the north of the region, and running south all the way to the Missouri-Arkansas border. Once the state of Arkansas completes its 30 mile portion of U.S. 67 from the Missouri state line to Walnut Ridge, the region will be connected by freeway-level highway all the way to Little Rock, AR.

US 67 and I-55 are the primary north-south transportation corridors. Both have daily traffic counts of nearly 10,000 vehicles. Highway 32 is the primary connector between the two corridors.