The city is named after King Louis IX of France. St. Louis is known by the nickname of The Gateway to the West. The city was the last major stop before pioneers journeyed Westward to the Pacific coast. The city also played a large part during the steamboat era due to its position at the confluence of the Mississippi River and the Missouri River. St. Louis was acquired from France by the United States during President Thomas Jefferson's term in 1803 as part of the Louisiana Purchase. The transfer of power from Spain was made official in a ceremony called, "Three Flags Day." On March 8, 1804, the Spanish flag was lowered and the French one raised. On March 10, the French flag was replaced by that of the USA. In 1904, St. Louis hosted that year's World's Fair and the Summer Olympic Games. Many of the parks, buildings, and finer homes in St. Louis were built around this time period. While there are few, if any, living residents who attended the Fair, it holds an important place in the modern development of the city.

Before Detroit became America's automotive capital, St. Louis was the largest producer of American automobiles in the early part of the 20th century. Midtown and Downtown still have many of the original warehouses and factories standing, but most have been converted to other purposes, such as loft apartments, shops and restaurants. St. Louis was also home to a bustling fashion manufacturing industry in the early 1900's, centered on Washington Avenue downtown. As with the auto industry, the last remnants of the fashion manufacturing industry can be found in the recently rehabbed warehouses which now contain new businesses and loft condominiums. In the late 20th century, St. Louis began a transformation from a manufacturing and industrial economy into a globally known center for research in medicine, biotechnology, and other sciences. Firms such as Monsanto, Centene, Solae, Energizer, Enterprise Rent-A-Car, Edward Jones, Wells Fargo Advisors (formerly A.G. Edwards), Anheuser-Busch/Inbev are headquartered in St. Louis. AT&T and Bank of America operate major regional offices here. Two major private research universities, Washington University in St. Louis and Saint Louis University, are an important part of the local economy and society.

St. Louis is truly a city of neighborhoods, each with its own distinct flavor and culture. There are 79 government-designated neighborhoods within the City of St. Louis, many of which have associations and councils that exercise wide control over development and subsidies from the highest to the very lowest local level. Some neighborhoods contain avenues of massive stone mansions built as palaces for heads of state visiting the 1904 World's Fair, and now occupied by some of the more wealthy families and individuals in the City of St. Louis. Other neighborhoods are predominantly middle class and working-class and have retained their singular cultural identity for 200 years. Today, most of them have endured as strong and cohesive communities for their residents.