The expedition led by Meriwether Lewis and William Clark, in 1804-1806, was the first American exploration to investigate the territory between the Mississippi River and the Pacific Ocean. Not tied to the Louisiana Purchase, the expedition had been planned and organized long before the purchase. Lewis and Clark were former army officers. The former was Jefferson's private secretary and the latter a good friend of Lewis. Initial plans were to leave St. Louis on May 14, 1804, travel up the Missouri River as far as the Rocky Mountains by winter, cross the "short portage" from the Missouri to the Columbia, and descend that river to the Pacific in the spring of 1805.

They further planned to retrace their steps and return to St. Louis by the autumn of 1805. By November 1804 they had only reached central North Dakota and they spent the winter with the Mandan Indians. They left in April, accompanied by Sacajawea, a Shoshoni woman translator. Their trip through the Rockies convinced the party there was no water route to the Pacific. They reached the mouth of the Columbia River in November 1805. The return trip was begun in March 1806. At the Continental Divide they split, with Lewis leading a party down the Missouri River and Clark a party down the Yellowstone River. The rejoined August 12 on the Missouri and reached St. Louis on September 23.