The first settler of Mississippi County was a John Johnson who arrived around 1800. Edward Matthews with his sons, Edward N., Charles and Joseph settled Matthews Prairie shortly afterward, and were joined there in the next two or three years by Charles Grey, Joseph Smith, John Weaver, George Hecker, and Absolom McElmurry.

About 1802 Abraham Bird, founder of Cairo, crossed the river and established himself on the land previously held by John Johnson. He established a business there and was an agent for some of the large shippers of that day.

In 1812 Newman Beckwith came from Virginia and located between Norfolk and Wolf Island. About 1800 James, John and Andrew Ramsey came from Cape Girardeau district and settled in the neighborhood of Norfolk. In 1813 William Rush settled on Rush Ridge and about 1800 James Lucas settled Lucas Bend.

John and Drakeford Grey and Thomas Phillips were pioneers of Wolf Island Township and William B. Bush of Long Prairie.

By 1805 six families had arrived on Matthews Prairie just north of where Charleston, Missouri now stands. By 1830 there were quite a few families on the Matthews Prairie.

The Bird family, one of the very earliest to settle in the County, developed a very lively mercantile business at the junction of the two rivers, and were receiving and forwarding agents for shippers breaking their cargo at this point. Here boats on the New Orleans - St. Louis runs unloaded goods destined for and picked up consignments from the East for delivery at Mississippi River ports.

Records mention Abraham Bird in 1811 as agent at Birds Point near the mouth of the Ohio, loading and unloading Christian Welts' flatboats from St. Louis or his keelboats that plied the Ohio River. Welts was a leading merchant from St. Louis.

On November 12, 1834, Isaac Sheppard obtained from the U.S. Government the SW half of section 3-26-16 containing 160 acres. On November 12, 1834 Isaac Sheppard and Mary Sheppard sold to Thankful Randol 80 acres of this land for a consideration of $100.

On May 13, 1837 Thankful Randol sold 22 1/2 acres to Joseph Moore for $337 and Charleston was immediately laid out. Its original boundary was 12 blocks - four north and south and three east and west.

The south border was what is now Marshall Street, the north border what is now Commercial Street, the east border is now First Street, and the west border is now Franklin Street.