Violent native resistance to Euro-American occupation of the Ohio Valley characterized the settlement period of West Virginia history, from the 1750s to the 1790s. When European or colonial governments were directly engaged, specific conflicts acquired formal names, such as the French and Indian War (1754—63), Pontiac's Rebellion (1763), and Lord Dunmore's War (1774). But notwithstanding the large-scale engagements and formal treaties that marked the named episodes, raids and counter-raids by small groups of fighters were typical of the period, and hostilities constantly occurred outside of the boundaries implied by the European system of naming and dating. "Border warfare," the term used by Alexander Scott Withers in his classic account of the period, is a more apt description of what actually took place.

The border in question was the territory drained by the Ohio River from its forks (modern Pittsburgh) to its falls (modern Louisville.) Contested between Britain and France until the French withdrew from North America in 1763, the Ohio then became both a boundary between white and Indian territory as well as the principal route of Euro-American advance and also of peaceful contacts among the two peoples. Ambushes and pursuits along the banks of the river were frequently reported, even after whites began to move north across the old border into the Indians' Ohio lands in the late 1780s. More than a thousand people on both sides were killed along the river during the decade that followed the American Revolution.

Indian raids usually struck at the western edge of white settlement, which meant that the fighting shifted from east to west: from the Greenbrier, upper New River, and upper Potomac valleys during the 1750s into the 1770s, to the Monongahela country (which then included the present Northern Panhandle) during the 1770s and 1780s, to the Kanawha and middle Ohio valleys, including Kentucky, during the 1780s and 1790s. But no part of the frontier was entirely safe until Indians began withdrawing from their Ohio homelands after the Treaty of Greenville in 1795.

Cultural contact and exchange were as common as conflict. This included genetic exchanges, trade in firearms and alcohol, armed encounters while hunting, and numerous other occasions where intercultural friction might lead to bloodshed.

Pitched battles such as occurred at the Monongahela (1755), Point Pleasant (1774), and Fort Henry (Wheeling; 1777, 1782) were the exceptions rather than the rule in border warfare. Generally the conflict exhibited the classic forms of guerrilla war: raids, ambushes, sneak attacks, massacres, and atrocities on both sides.

Euro-American authorities frequently engaged native leaders in negotiations, seeking to head off problems short of warfare (as well as to advance white interests regarding trade and land). However, leaders on both sides admitted difficulty in restraining their "foolish young men," as the Indians usually put it. Another defensive strategy was the building of frontier forts, which were of two types: garrisons established at key points near the western edge of settlement, such as Fort Pitt (at present Pittsburgh, established in 1758), Fort Fincastle (later Fort Henry, Wheeling; 1774), Fort Randolph (Point Pleasant; 1776), Fort Harmar (Marietta, Ohio; 1784), and Fort Lee (Charleston; 1788); and neighborhood forts in which settlers could seek shelter in times of Indian alarm. "Forting" became a formative frontier experience for generations of settlers.

When whites went on the offensive it was usually in direct immediate response to an Indian raid that had resulted in captives, or it was a larger military expedition that sought to find and destroy the Indian villages in Ohio from which the native raiders came. As often as not, these large-scale expeditions were unsuccessful, as in Braddock's Campaign and the Sandy Creek Expedition of the 1750s or the disastrous forays into the Ohio country led by Col. William Crawford (1782) and Gen. Arthur St. Clair (1791). Andrew Lewis's campaign of 1774 culminating in the Battle of Point Pleasant and Gen. Anthony Wayne's invasion of Ohio that led to victory at Fallen Timbers (1794) were successful examples of this "search and destroy" strategy.

Both sides furnished examples of warrior-heroes. Among the Indians were the Seneca Corn planter (1737?—1835) and the Shawnee Cornstalk (d. 1777), both of whom were celebrated warriors who later became political leaders. White Indian fighters associated with West Virginia include Daniel Boone (1734—1820), Samuel Brady (1758—1796), Jesse Hughes (1750—1829), and especially Lewis Wetzel (1763—1808), "the Boone of northwestern Virginia." According to his modern biographer, Daniel Boone killed only three Indians during an entire lifetime on the frontier, thanks to his Quaker values and good-natured respect for the natives. Wetzel, on the other hand, was a classic frontier Indian hater, who is known to have hunted Indians for sport as well as defense.

The accounts of these and other heroes that Joseph Doddridge, Withers, and others made available to 19th-century readers were full of stalwart action and thrilling escapades, combined with frightening tales of Indian savagery and cruelty. However, an examination of treaty documents and reminiscences such as those collected by Lyman Draper shows that frequently white captives came to prefer life among the natives. This was especially true of younger men and older women, who seem to have valued the relative equality of Indian life over the patriarchal order of Euro-American culture. Sometimes such people were forcibly repatriated as a result of treaties; more often their experience of cultural conflict played out in private lives. Draper collected the story of William Renick, who spent a lifetime tracking down a younger brother taken captive by Shawnees in 1761, only to have the younger man reject the comforts of a prosperous Greenbrier Valley home when at last Renick located him. Instead, after a short stay with his brother, the former captive slipped away to his Indian home in Ohio one night, leaving his European clothing neatly folded on a chair. The descendants of Mary Draper Ingles, whose captivity and perilous escape across southern West Virginia in 1755 was a prelude to the Sandy Creek Expedition, reported that in her old age she sat in melancholy silence next to the fireplace, keeping to herself whatever memories lingered of her personal experience of border war.