Ste. Genevieve to Harrisonburg: Ultimate Road Trip Guide

Ste. Genevieve, Missouri, founded around 1735 by French Canadian settlers, stands as one of the oldest permanent settlements west of the Mississippi River. Its National Historic Landmark district features 18th-century French colonial vertical-log houses, unlike anywhere else in the United States. Harrisonburg, Virginia, by contrast, anchors the fertile Shenandoah Valley, a region once traversed by Native American trails and later by Civil War armies.

This 750-mile route primarily traces Interstate 64 eastward, crossing the Mississippi River into Kentucky, traversing the rolling hills of West Virginia, and finally dropping into the valley of Virginia. The drive typically takes about 11-12 hours without stops, but the journey rewards those who linger with unexpected landscapes.

Notable: the route passes through the historic Bluegrass region of Kentucky, bisects the Daniel Boone National Forest, and skirts the edge of the George Washington & Jefferson National Forests before reaching Harrisonburg.

The primary highway is Interstate 64, which runs east-west from St. Louis to Virginia Beach. From Ste. Genevieve, take MO-32 east to join I-64 east near Mt. Vernon, Illinois. The route continues through Louisville, Kentucky; Lexington, Kentucky; Charleston, West Virginia; and then into Virginia via I-81 north to Harrisonburg.

• Fuel costs vary: expect $3.50-$4.00/gallon on average. Kentucky often has lower fuel prices than Missouri or Virginia.
• Tolls: minimal or none on I-64 except possible bridge tolls (Mississippi River bridge near St. Louis is free on I-64).
• Rest areas are abundant every 30-40 miles along I-64 in Kentucky and West Virginia, many with picnic tables and restrooms.
• Urban traffic: avoid Louisville between 4-6 PM; Lexington has moderate congestion near the New Circle Road (KY-4) junction.

Just off I-64 in Kentucky, the town of Midway (exit 65) is a historic railroad community with a main street full of artisan shops and the Midway School of Equine Science. Further east, the Whitewater Memorial State Park in Indiana (near Richmond, exit 156A) has a small but picturesque lake with hiking trails.

In West Virginia, the Greenbrier Valley has the Lost World Caverns in Lewisburg (exit 175), a commercial cave with massive stalagmites. Near the Virginia border, the town of White Sulphur Springs (exit 181) is home to the luxurious Greenbrier resort, but the historic district is walkable and free.

As you approach Harrisonburg, consider a detour to the Shenandoah National Park entrance at Thornton Gap (US-211 east from I-81 exit 32), for sunset views over the Valley.

Discover more tips: how to find the best stops and hidden gems between cities.

I-64 is well-maintained throughout, but West Virginia sections have steep grades and sharp curves, especially near the Sandstone Mountain (mile marker 139). Speed limits drop to 65 mph in mountainous areas. Use lower gears for descent to avoid brake fade.

• Family-friendly stops: The Louisville Mega Cavern (exit 10 off I-64) offers underground bike trails and a ropes course. In the summer, the Kentucky Splash Waterpark in Bardstown (exit 34) provides cooling off.
• Pet-friendly: Almost all rest areas allow pets on leash; the Berea rest area (mile 77) has a fenced pet exercise area. For overnight stay, Red Roof Inn in Lexington (exit 108) welcomes pets.
• Fatigue management: Use the rest areas at mile 18 (Mammoth Cave welcome center) and mile 174 (Beckley, WV). Both have picnic shelters and walking paths.

From the Mississippi floodplain, the route climbs into the Knobs region of Kentucky—cone-shaped hills that give way to the Bluegrass region, known for rolling horse pastures and limestone fences. In West Virginia, I-64 traverses the Appalachian Plateau with dramatic cuts through sandstone and shale, offering long-range vistas at overlooks like Hawks Nest State Park (near Gauley Bridge, WV).

• Key natural stop: Natural Bridge State Park in Kentucky (exit 20 on I-64), a 65-foot-high natural sandstone arch with walking trails.
• Bluegrass horse farms: Visitors can spot thoroughbred farms along I-64 near Lexington, especially between exits 58 and 77.
• Local commerce: Lexington's Cardinal Hill produces handmade pottery, and in Lewisburg, WV, browse antique shops on Washington Street.