Native Americans have lived along the Mississippi River and its tributaries for thousands of years. Most were hunter-gatherers, but some, such as the Mound Builders, formed prolific agricultural societies. The arrival of Europeans in the 16th century changed the native way of life as first explorers, then settlers, ventured into the basin in increasing numbers. The river served first as a barrier, forming borders for New Spain, New France, and the early United States, and then as a vital transportation artery and communications link. In the 19th century, during the height of the ideology of manifest destiny, the Mississippi and several western tributaries, most notably the Missouri, formed pathways for the western expansion of the United States.
Formed from thick layers of the river's silt deposits, the Mississippi embayment is one of the most fertile regions of the United States; steamboats were widely used in the 19th and early 20th centuries to ship agricultural and industrial goods. During the American Civil War, the Mississippi's capture by Union forces marked a turning point towards victory, due to the river's strategic importance to the Confederate war effort. Because of substantial growth of cities and the larger ships and barges that replaced steamboats, the first decades of the 20th century saw the construction of massive engineering works such as levees, locks and dams, often built in combination. A major focus of this work has been to prevent the lower Mississippi from shifting into the channel of the Atchafalaya River and bypassing New Orleans.
Since the 20th century, the Mississippi River has also experienced major pollution and environmental problems – most notably elevated nutrient and chemical levels from agricultural runoff, the primary contributor to the Gulf of Mexico dead zone.
The word Mississippi itself comes from Misi zipi, the French rendering of the Anishinaabe (Ojibwe or Algonquin) name for the river, Misi-ziibi (Great River).
In the 18th century, the river was the primary western boundary of the young United States, and since the country's expansion westward, the Mississippi River has been widely considered a convenient if approximate dividing line between the Eastern, Southern, and Midwestern United States, and the Western United States. This is exemplified by the Gateway Arch in St. Louis and the phrase "Trans-Mississippi" as used in the name of the Trans-Mississippi Exposition.