From the 1750s to the 1790s, violent Indian resistance shaped West Virginia’s history. Major conflicts like the French and Indian War and Lord Dunmore's War, along with frequent raids and ambushes, defined this era of "border warfare" along the contested Ohio River region.

Fighting gradually shifted westward, and while trade did occur at times, most of the conflict took the form of guerrilla warfare. Settlers built forts and tried to negotiate with Native leaders, but controlling young warriors on both sides was difficult. Notable Native defeats occurred at Point Pleasant (1774) and Fallen Timbers (1794).