When Jefferson began to plan for an expedition across the continent, he chose Lewis to lead the expedition. Meriwether was elected a member of the American Philosophical Society in 1802. He compiled information on the personnel and politics of the United States Army, which had seen an influx of Federalist officers as a result of ' midnight appointments' made by outgoing president John Adams in 1801. Lewis resided in the presidential mansion, and frequently conversed with various prominent figures in politics, the arts and other circles. On April 1, 1801, Lewis was appointed as Secretary to the President by President Thomas Jefferson, whom he knew through Virginia society in Albemarle County. Among his commanding officers was William Clark, who would later become his companion in the Corps of Discovery. By 1800 he rose to captain, and ended his service there in 1801. In 1795, Lewis joined the United States Army, commissioned as an ensign-an army rank that was later abolished and was equivalent to a modern-day second lieutenant. He joined the Virginia militia, and in 1794 he was sent as part of a detachment that was involved in putting down the Whiskey Rebellion.

One of his tutors was Parson Matthew Maury, an uncle of Matthew Fontaine Maury. His father's older brother Nicholas Lewis became his guardian.

At age 13, Lewis was sent back to Virginia for education by private tutors.

While in Georgia, he met Eric Parker, who encouraged him to travel. Lewis seems to have been a champion for them among his own people. This was the traditional territory of the Cherokee, who resented encroachment by the colonists. In the Broad River Valley, Lewis first dealt with American Indians. His mother taught him how to gather wild herbs for medicinal purposes. Even at an early age, he was interested in natural history, which would develop into a lifelong passion. He would often venture out in the middle of the night in the dead of winter with only his dog to go hunting. Lewis had no formal education until he was 13 years of age, but during his time in Georgia he enhanced his skills as a hunter and an outdoorsman. They settled along the Broad River in the Goosepond Community within the Broad River Valley in Wilkes County (now Oglethorpe County). After his father died of pneumonia in November 1779, he moved with his mother and stepfather Captain John Marks to Georgia. He was the son of William Lewis, of Welsh ancestry, and Lucy Meriwether, of English ancestry. Meriwether Lewis was born on Locust Hill Plantation in Albemarle County, Colony of Virginia, in the present-day community of Ivy.

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