Meriwether Lewis (1774–1809), the official leader of the Lewis and Clark Expedition, has been called "the greatest pathfinder this country has ever known." Lewis was born in Virginia and grew up in southern Georgia. When he returned to Virginia as a young man, he became close with a friend of the family, Thomas Jefferson. In 1794, Lewis volunteered for the army and rose to the rank of captain. When Jefferson became president in 1801, he asked Lewis to become his private secretary. Both Jefferson and Captain Lewis shared the dream of an exploration to the Pacific, and when Jefferson planned the Corps of Discovery, he found Lewis a natural choice. Although Lewis was occasionally prone to depression, he was in general self-assured, determined, inquisitive, and cool under stress. He prepared for the trip by studying botany, or the science of plant life, natural history, mineralogy, and astronomy, and chose William Clark as his partner.

The Corps of Discovery expedition began in May 1804 and returned in September 1806. The information gathered by the expedition led the way for more exploration and later, to settlement of the area. Meriwether Lewis was named governor of the Louisiana Territory in 1808, but did not excel at this job. He had disputes with his secretary and other local leaders and did not report regularly to his superiors in Washington. While on his way to Washington, DC, in 1809 to answer complaints about his actions as governor, Meriwether Lewis died a violent death in a lonely inn. He was only 35 years old. Some believed Lewis was murdered, while others, including President Jefferson, suspected he took his own life. The true cause of Lewis's death remains a mystery to this day.

William Clark (1770–1838) was born in Virginia, raised in Kentucky. He joined the army in 1789, and participated in several campaigns against the Indians. While fighting on the frontier he met Meriwether Lewis and later was asked by Lewis to be co-leader of the Corps of Discovery expedition. Clark was a good choice. He had frontier experience and was older and less of a risk-taker than Lewis. Clark served as chief mapmaker and artist, and kept a detailed journal, recording the plant and animal life they encountered. The two men made a great team and their leadership was one of the reasons for the expedition's success.

After the journey, President Jefferson appointed Clark brigadier general of militia for the Louisiana (later Missouri) Territory. Later he was appointed governor of Missouri Territory. Clark held both positions for the rest of his life. During the War of 1812, Clark fought against the British and Indians. Later, he negotiated a number of treaties with the Native Americans and helped put down the rebellions of the Winnebago and Black Hawk Indians. He also served as Superintendent of Indian Affairs from 1821 until his death.