Sanford is a city in the central region of the U.S. state of Florida and the county seat of Seminole County. As of the 2010 census, its population was 53,570. Known as the "Historic Waterfront Gateway City," Sanford sits on the southern shore of Lake Monroe at the head of navigation on the St. Johns River. Native Americans first settled the area thousands of years before the city was formed. The Seminoles arrived in the area in the 18th century.