Louisville is Kentucky's largest city. The settlement that became the City of Louisville was founded in 1778 by George Rogers Clark and is named after King Louis XVI of France. Louisville is famous as the home of "The Most Exciting Two Minutes in Sports": the Kentucky Derby, the widely watched first race of the Triple Crown of Thoroughbred Racing.

Louisville is situated in north-central Kentucky on the Kentucky-Indiana border at the only natural obstacle in the Ohio River, the Falls of the
Ohio. Louisville is the county seat of Jefferson County, and since 2003, the city's borders are coterminous with those of the county due to merger. Because it includes counties in Southern Indiana, the Louisville metropolitan area is regularly referred to as Kentuckiana. A resident of Louisville is referred to as a Louisvillian. Although situated in a Southern state, Louisville is influenced by both Midwestern and Southern culture, and is commonly referred to as either the northernmost Southern city or the southernmost Northern city in the United States.

Recently, Louisville has emerged as a major center for the health care and medical sciences industries. Louisville has been central to advancements in heart and hand surgery as well as cancer treatment. Some of the earliest artificial heart transplants were conducted in Louisville. Louisville's thriving downtown medical research campus includes a new $88 million rehabilitation center, and a health sciences research and commercialization park that, in partnership with the University of Louisville, has lured nearly 70 top scientists and researchers.