Before the European invasion of North America, the Cherokees were probably the largest indigenous society in the region that became the U.S. Southeast. Numbering around 20,000, they lived comfortably in the southern Appalachian Mountains, drawing on the wildlife and food resources of the diverse forest surrounding their villages and the rich soils they cultivated in sheltered mountain coves and river bottoms. Even after European diseases and warfare reduced their numbers by as much as 75 percent, the Cherokee remained a potent force in warfare and diplomacy. Their geographic location in the western Carolinas, north Georgia, and eastern Tennessee allowed them to play off rival European powers against each other and to command a lucrative share of the trade in pelts and deerskins bound for ports in Virginia and South Carolina. Despite lost wars in 1760—62 and again during the American Revolution, they retained their independence and much of their landed patrimony. It was not until the U.S. government forcibly removed most of the Cherokee from their homeland that this society ceased to play a major role in the history of the American south.

Although the Cherokee claimed land south of the Great Kanawha River in present West Virginia, they did not depend on it for hunting and relinquished this claim in the Treaty of Hard Labor and the Treaty of Lochaber in 1768 and 1770. They used the Great Appalachian Valley corridor to fight and trade with their fellow Iroquoian language speakers in New York and Pennsylvania, and on at least one occasion engaged in a great battle with these enemies at a place near modern Shepherdstown. Cherokees also briefly played a role as allies of Western Virginia frontiersmen in the ill-fated Sandy Creek Expedition of 1756. Otherwise they did not threaten the Ohio Valley except in the upper New River area of present southwest Virginia. Young men responded to the entreaties of Mingo and Shawnee warriors to join in their assaults during the Indian wars that accompanied and followed the Revolution, but these were the actions of individuals, not of the Cherokee leadership.

Cherokees who were active in West Virginia were almost always members of the Overhill towns, one of five clusters of villages among which their people were distributed. The Overhill Cherokees lived along the Little Tennessee River in East Tennessee. The Middle and Valley towns were located south of the Great Smoky Mountains in what is now western North Carolina. The other clusters were located east of the mountains, in the foothills of the South Carolina and Georgia Blue Ridge.

Given the limited role that Cherokees played in West Virginia history, it is curious that a claim of Cherokee ancestry developed among many families in the Mountain State. This may be because after their 19th century "renaissance," the Cherokees were better known and more widely admired than the other Indian societies—such as Shawnee or Delaware—who are more likely to have participated in genetic exchanges on the Western Virginia frontier. Demographically, it is more probable that claims of Indian blood actually masked African-American ancestry. A third possible explanation comes from the migration of young Cherokee men from their North Carolina reservation during the late 19th and early 20th centuries. Other southerners, white and black, migrated north to West Virginia lumber and coal camps during this period, and it is possible that Cherokee migrants chose the same paths.