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Pemiscot County is located in the southeastern part of Missouri, bordering the state of Arkansas. The county was established in 1851, named after the Pemiscot tribe, who were indigenous to the area. Originally, the region was predominantly swamp and forest, and was sparsely settled by European colonizers until the late 19th century.

The early settlers in Pemiscot County were primarily farmers, who quickly recognized the area's fertile soil and abundant natural resources. The growth of the agriculture industry, particularly cotton farming, played a significant role in the county's development. The construction of railroads in the late 19th century further facilitated the transportation of goods and helped the county thrive economically.

Throughout the early 20th century, Pemiscot County experienced both booms and busts. The cotton industry flourished during prosperous times, but suffered during the Great Depression. The county also faced challenges related to flooding, as the Mississippi River borders its eastern boundary. The construction of levees and drainage systems has been an ongoing effort to mitigate the impact of flooding in the region.

Today, Pemiscot County continues to be largely rural and heavily reliant on agriculture. While cotton farming remains significant, there has been diversification into other crops, such as soybeans and corn. The county also faces economic challenges and a declining population, prompting efforts to attract new industries and improve infrastructure. Despite these challenges, Pemiscot County maintains a strong sense of community, with a rich history tied to its agricultural roots.