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In the winter of 1540 Hernando de Soto led a large expedition into Mississippi and wintered along the Pontotoc River. In the following spring he reached the Mississippi River, but, because he found no gold or silver in the region, Spanish explorers directed their efforts elsewhere.

Nearly 130 years later a small group of French Canadians sailed down the Mississippi River and immediately realized its commercial and strategic importance. In 1699 a French expedition led by Pierre le Moyne d'Iberville established France's claim to the lower Mississippi valley. French settlements were soon established at Fort Maurepas, Mobile, Biloxi, Fort Rosalie, and New Orleans.

Following the French and Indian War, which ended in 1763, France ceded its possessions in the lower Mississippi valley, except New Orleans, to Great Britain, which also gained possession of Spanish Florida and divided that territory into two colonies. One of those was West Florida, which included the area between the Apalachicola and Mississippi rivers. The original northern boundary of West Florida was the 31 parallel, but it was extended in 1764 to the 3228' parallel. Fort Rosalie was renamed Fort Panmure, and the Natchez District was established as a subdivision of West Florida. Natchez flourished during the early 1770s. After the outbreak of the U.S. War of Independence, Spain regained possession of Florida and occupied Natchez. The Treaty of Paris of 1783 fixed the 31 parallel as the boundary between Spanish Florida and the United States, but Spain continued to occupy Natchez until the dispute was settled in 1798.

The original Mississippi Territory created by the U.S. Congress in1798 was a strip of land extending about 100 miles north to south and from the Mississippi River to the Chattahoochee on the Georgia border. The territory was increased in 1804 and 1812 to reach from Tennessee to the Gulf. In 1817 the western part achieved statehood as Mississippi (the eastern part became the state of Alabama in 1819). Natchez, the first territorial capital, was replaced in 1802 by nearby Washington, which in turn was replaced by Jackson in 1822.