Following years of land encroachments by American settlers, Chief Little Turtle of the Miami leads the Indian Nations of the Northwest Confederacy to a major victory over the fledgling U.S. Army. But a new force under General "Mad" Anthony Wayne embarks on a counteroffensive, leading to a final battle that will see the Confederacy defeated - and open a new era of westward expansion.

After building his reputation as a formidable hunter on Lewis and Clark's Expedition into the newly acquired Louisiana Territory, John Colter chooses to stay out in the wilderness and enter the booming fur trade. But when he repeatedly ignores warnings from the Blackfeet not to hunt their sacred beaver on their lands, he's taken captive and forced to make a run for his life.

Missionaries Marcus and Narcissa Whitman settle by the Columbia River to convert the Cayuse. Cultural clashes and a measles outbreak increase tensions, leading to a fateful confrontation.