Manuel Lisa was not the only person of Spanish descent to be involved in the American fur trade, but he was certainly the most notable. He was born in New Orleans on September 8, 1772. His mother and father were both Spanish and his father, Christopher, was a Spanish government official. Little is now known of the family or of Manuel's childhood. It is believed that Manuel was engaged in the fur trade from an early age and went to St. Louis, Missouri, in about 1790. In 1800 the Spanish government, presumably through the influence of his father, granted him the exclusive right to trade with the Osage Indian tribe in place of Pierre Chouteau who had held the grant previously. Shortly thereafter, Spain secretly transferred Louisiana Territory to France and Napoleon Bonaparte went on to sell it to President Thomas Jefferson. In 1807 Lisa, now living in territory owned by the United States, built a trading post on the Missouri River at the mouth of the Bighorn.
Returning to St. Louis in 1808, Lisa was involved in forming the St. Louis Missouri Fur Company during the winter of 1808-1809. In the spring of 1809 he returned to his trading post on the Bighorn, transferred it to the new company, and spent that season and the following one there. Both years he wintered in St. Louis. In the spring of 1811 Wilson Price Hunt led the American Fur Company's Astorian land party upriver ahead of Lisa. Lisa, starting nineteen days and two hundred forty miles behind Hunt, pursued and caught up with him at the Mandan Indian villages on the upper Missouri. In so doing, Lisa set an amazing speed record for a keel boat. He and his twenty handpicked crew dragged, poled, rowed, and sailed their craft eleven hundred miles upriver in two months time averaging an unheard of eighteen miles per day. Lisa returned to St. Louis in October 1811, and participated in the reorganization of the Missouri Fur Company. After wintering in St. Louis he spent the 1812 season as well as that winter in the Mandan Indian villages.
Returning to St. Louis on June 1, 1813, Lisa learned that war had broken out between the United States and Great Britain. Because of his great familiarity with the Indians of the upper Missouri, Lisa was made sub-agent for all Indian tribes living north of the Kansas. He was specifically instructed to maintain their friendship with the United States and to resist the subversive activities that were expected from British agents operating out of Canada. Lisa may have visited the Omaha Indian Nation in 1813 and definitely spent the summer of 1814 and the following winter in Fort Lisa near present day Omaha, Nebraska. During this period, he married a woman known variously as Mary or Polly Charles. Legend has it that Polly had been a prisoner of Indians and he wed her out of pity. Polly and Manuel had three children together only one of which survived to adulthood. In 1814, while still married to Polly, he took the daughter of an Omaha Indian chief to wife and had a son with her.
In 1815 and 1816 Lisa visited St. Louis in the summer and wintered at Fort Lisa. In 1817 he resigned his commission as Indian sub-agent and through various reorganizations of the Missouri Fur Company became it's president. Polly died that same year. Lisa knew the upper Missouri as well or better than any man then alive, he generally got along well with Indians, was universally respected for his trading acumen, but intensely disliked by his various competitors in the fur trade. His own activities and that of his enterprise, the Missouri Fur Company, helped open the vast unexplored territory that Jefferson had purchased from Napoleon. He married for the second time on August 5, 1818. His new wife was Mary Hempstead, the widow of John Keeny. She spent the winter of 1819-1820 at Fort Lisa with Manuel and they were very happy together.
Lisa returned to St. Louis in April 1820. A few weeks later he became seriously ill and, on August 12, 1820, died. Mary Hemstead Lisa, known as "Aunt Manuel," outlived her husband. Both are buried in St. Louis.