By 1760, the St. Louis area had been settled by Mississippian Native American mound builders who lived nearby in Cahokia (and disappeared around the 15th century), as well as, tribes including the Illini, the Missouria and the Osage tribes. In 1762, Spain gained control of the Louisiana Territory in the Treaty of Fontainebleau.

In response to the police shooting and subsequent unrest in Ferguson, the U.S. Department of Justice investigates policing practices in St. Louis.