During this period, the powerful nations of the Iroquois Confederacy, based in New York, had maintained control of much of the Ohio Valley as hunting grounds by right of conquest after defeating other tribes.By the terms of the 1768 Treaty of Fort Stanwix, the Penns were allowed to purchase the modern region from the Iroquois.

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Michael Bezallion was the first to describe the forks of the Ohio in a 1717 manuscript, and later that year European fur traders established area posts and settlements.

During 1753–54, the British hastily built Fort Prince George before a larger French force drove them off.

Lord Jeffrey Amherst ordered blankets contaminated from smallpox victims to be distributed in 1763 to the tribes surrounding the fort.

The disease spread into other areas, infected other tribes, and killed hundreds of thousands.

British General Edward Braddock was dispatched with Major George Washington as his aide to take Fort Duquesne.

The British and colonial force were defeated at Braddock's Field.

In 1784, Thomas Viceroy completed a town plan which was approved by the Penn family attorney.

Pittsburgh became a possession of Pennsylvania in 1785.

After a public campaign the original spelling was officially restored by the United States Board on Geographic Names in 1911.