The white settlers who were passing through the area carried small pox with them. Members of the Walla Walla and Cayuse tribes became angry when large amounts of their population began getting sick. Whitman was a surgeon and tried to help, but the medicine he gave was ineffective. The tribes saw that none of the whites were dying, yet two hundred Native Americans had died after getting medicine from Whitman. This lead to tribal leaders meeting in council and agreeing the doctor should be killed. It was a common practice in the Columbia Plateau to kill someone who was believed to be misusing their spirit power.

Whitman had learned about threats to the settlement but refused to evacuate. On November 29, 1847, members of the Cayuse tribe attacked. After three days, 13 white settlers, including Whitman and his wife, were murdered. Some whites escaped while others were taken hostage. The Hudson Bay Company at Fort Walla Walla traded blankets, shirts, guns and ammunition for release of the hostages.

When news of the massacre reached Washington DC, Congress was prompted to create the Oregon Territory. A group of Oregon Volunteers chased the Cayuse tribe into the mountains. Other tribes of the area refused to join in the fight against the whites. Chief Tilaukait and five other men surrendered themselves as principal murderers of the Waiilatpu in order to protect the rest of the Cayuse tribe. The men were convicted and hung. The Cayuse tribe was removed to the Umatilla Reservation in Oregon and dissolved among other tribes. Eventually their language and identity were lost.