When the first Europeans came to North America, they soon became aware of a network of pathways extending from the Gulf Coast to the Great Lakes and everywhere in between. These pathways, or Indian trails, served as a means of interaction between Native American groups in various cultural regions. The remnants of trails that once crossed what is now West Virginia are links along these major Indian thoroughfares.

There was a long-distance trade network in place throughout North America for thousands of years. Marine shell and native copper were traded between the Great Lakes region and the Gulf Coast as early as 6000 B.C. In the Ohio Valley, copper ornaments and marine shell beads have been found at Adena mounds dating from 400 to 200 B.C. Many of the routes used by these early groups were still in use when the first European settlers arrived, and frequently these same routes became major highways. Some are still in use today.

In the 1920s, William E. Myer, working for the Bureau of American Ethnology, began a study of colonial period Indian trails in the Southeast. Myer died before his work was published, but his efforts produced a map illustrating regional interaction pathways, several of which span West Virginia. Most of the regional trails also have local names.

The Great Indian Warpath was one of the most important north-south trails in eastern North America. The route originated in the Southeast, in Creek territory, and extended north through eastern Tennessee, where it split into the Ohio Branch and the Chesapeake Branch. The Ohio Branch continued through southwestern Virginia, to the New River, then along the Kanawha River to the Ohio River, where it met other important trails and continued north to Lake Erie. The portion of the trail that followed the Kanawha River is also called the Kanawha or Buffalo Trail. The Midland Trail, U.S. 60, part of which was also the Kanawha Trail, follows the course of another old Indian trail from the Kanawha Valley to Virginia.

The Chesapeake Branch of the Great Indian Warpath proceeded north through the Valley of Virginia. This route, also called the Warrior Path, passed through present West Virginia for only a short distance in the Eastern Panhandle, where it paralleled modern Interstate 81 and U.S. 11.

There were numerous other Indian trails throughout Western Virginia. Many followed the river valleys, including the Paint Creek Trail, the Big Sandy Trail, the Guyandotte Trail, the Coal River Trail, and the Little Kanawha Trail. The Scioto-Monongahela Trail connected Lower Shawnee Town, in Ohio, to the Monongahela Valley and proceeded north into Pennsylvania. U.S. 50 now parallels its approximate course. The Seneca Trail was another important north-south route that began in Seneca territory in New York and stretched south through Pennsylvania into Western Virginia, through the Tygart and Greenbrier valleys, to the New River. U.S. 219 parallels the main branch of the Seneca Trail in West Virginia.