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In 1836, two missionaries—Marcus and Narcissa Whitman—founded the Whitman Mission among the Cayuse Indians at Waiilatpu, six miles west of present-day Walla Walla, Washington. In addition to evangelizing, the missionaries established schools and grist mills and introduced crop irrigation. Their work advanced slowly until in 1842, Marcus Whitman convinced the American Board of Commissioners for Foreign Missions to provide support. Returning the following year, he joined approximately a thousand settlers travelling to Oregon Territory.

The sudden influx of white settlers led to an escalation of tension between natives and settlers, which owed much to cultural misunderstandings and mutual hostilities. For instance, the Cayuse believed that to plow the ground was to desecrate the spirit of the Earth. The settlers, as agriculturalists, naturally did not accept this. The Cayuse expected payment from wagon trains passing through their territory and eating the wild food on which the tribes depended; the settlers did not understand this and instead drove away the men sent to exact payment, in the belief that they were merely “beggars”.

The new settlers brought diseases with them. In 1847 an epidemic of measles killed half the Cayuse. The Cayuse suspected that Marcus Whitman—a practicing physician and religious leader, hence a shaman—was responsible for the deaths of their families, causing the disaster to make way for new immigrants. Seeking revenge, Cayuse tribesmen attacked the Whitman Mission on 29 November 1847. Fourteen settlers were killed, including both of the Whitmans. Most of the buildings at Waiilatpu were destroyed. The site is now a National Historic Site. For several weeks, 53 women and children were held captive before eventually being released.

This event, which became known as the Whitman Massacre, started the Cayuse War.