Sometimes referred to as "Scots-Irish" or "Ulster Scots," the Scotch-Irish were second only to the Germans in the settlement of the Eastern Panhandle. And they were the primary frontiersmen who trekked across the Alleghenies into much of the rest of West Virginia. The Scotch-Irish were also known for their pioneering in the Valley of Virginia, the Carolinas, Kentucky, Tennessee, and lands farther west.

The Scotch-Irish came to America from Ulster, or northern Ireland, which had been settled as a Protestant province primarily by Presbyterian Scots in the early 17th century. With each passing generation, these Ulster Scots took on their own culture and lifestyle. They were no longer Scottish Lowlanders, and certainly they were not Irish, their Catholic enemy. A hundred years after the Protestant settlement of Ulster, hard times and anti-Presbyterian laws would influence the emigration of more than 200,000 of these Scotch-Irish to America.

The great migration consisted of five different periods: 1717—18, 1725—29, 1740—41, 1754—55, and 1771—75. As many as half of these emigrants became indentured servants in America, which delayed their movement onto the frontier. Others, who had paid their own passage across the ocean, searched for land soon after arriving in America. The Scotch-Irish normally came to Pennsylvania because of its accessible ports, particularly Philadelphia, and the colony's record of liberal land policies and religious tolerance. As available land diminished in Pennsylvania, the Scotch-Irish next moved south into the rich Valley of Virginia. Often the sons and daughters of these settlers moved farther south and west.

By the middle of the 18th century, the Scotch-Irish had spearheaded settlements across the Alleghenies into present West Virginia. Western lands were opened to white settlement only after the British-American victory in the French and Indian War; the defeat of Pontiac's Rebellion, a massive Indian attack all along the frontier in 1763; and a series of treaties with the Indians. The American Revolution would soon bring further bloodshed to settlements west of the mountains. However, with the American victory over the British and their Indian allies, by the end of the 18th century the Allegheny region was again open to settlement. The Scotch-Irish would reap the rewards of victory as they expanded the white frontier farther across the Alleghenies.

As pioneers the Scotch-Irish were noted for their restless nature; their hardiness as hunters and settlers; their spirit of adventure; their strong Protestant faith (and yet their passion for drinking and gambling); their quick temper; their contempt for nobility and titles; and their ferocity toward the Indians. They came from an uprooted people, and they showed little mercy in uprooting others. The German pioneers were often better farmers, and their lands were usually superior. However, in time of war, or when quick action was demanded on the frontier, the Scotch-Irish were unmatched. No other ethnic group would be as significant in shaping the culture of West Virginia.