In the 1730’s, a Frenchman named Jean Baptiste Girardot, for whom Cape Girardeau is named, established a trading post on the west bank of the Mississippi River. In 1793, the Spanish Government gave Frenchman Louis Lorimier a land grant to establish another trading post near the river, a few miles south of the site previously established by Girardot. Population expansion at first was slow; however, the age of steamboats allowed easy movement of manufactured goods on the river, which expedited growth. When the railroads were completed, it is said that the city’s population doubled in just a few months.

Ste. Genevieve is the oldest permanent settlement in Missouri founded in the late 1740s about two miles south of its present location on the banks of the Mississippi River. Creoles from Canada and east of the Mississippi flocked to Ste. Genevieve after George III issued the Royal Proclamation of 1763. Following a flood in 1785, the town moved from its initial location immediately next to the Mississippi about a half-mile inland and two miles north. The most distinctive buildings during this period was the "vertical log" construction where walls of buildings were built based on posts dug into the ground.