The town of Cape Girardeau was established about 1793, while Missouri was part of Spanish Upper Louisiana. Founded and owned entirely by Frenchman Louis Lorimier, its name probably originates with a French ensign named Girardot, who was stationed at Kaskaskia in 1704. By 1804 only five French families remained; Americans comprised the vast majority of settlers. The town made remarkable progress from 1900 to 1910 when its population nearly doubled, reaching 8,545 residents.

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