It wasn't until 1836 that the first missionaries arrived on the Columbia Plateau, when the American Board of Commissioners for Foreign Missions sent out Reverend Samuel Parker and Marcus Whitman to scout potential mission sites in Oregon Country. That fall, Marcus and Narcissa Whitman founded a Protestant mission among the Cayuse at their village, Waiilatpu, along the Walla Walla River, near present-day Walla Walla, Washington. The Whitmans' travel companions, Eliza and Henry Spalding, created their Protestant mission in Nez Perce territory in the Lapwai Valley, near present-day Lewiston, Idaho.

The population of white settlers was slowly but steadily growing along the Columbia River in the late 1830s. A great number of them were "Americans" from the States, with various ethnic backgrounds. The next largest population segment of settlers chiefly consisted of French-Canadian, and some Scottish, Irish, English, and German fur traders. Many of them married Indian women and raised families of mixed-ancestry. Most of these traders were retired employees of the Hudson's Bay Company, born as British subjects, and of the Roman Catholic faith.

While the missionaries vied for their souls, the U.S. and Britain vied for their land. The U.S secured the territory from England in 1846, as if nobody lived there. No treaties had been established with scores of tribes who inhabited the Columbia Basin, yet their homelands were being traded out from under them. The U.S. government encouraged its citizens to move to Oregon territory without extinguishing the Indians' claims to the lands. Thousands of immigrants flooded into the region each year.

Although Catholic missionaries had been in the Oregon Country since 1838, the first mission wasn't established among the tribes of the Umatilla Reservation until 1847. St. Anne's was established along the Umatilla River in a cabin donated by the influential Cayuse leader Taawitoy . Within just a few years, there were three Catholic missions in the area; St. Anne's, one at Mission, and St. Rose, near Walla Walla, all in traditional Cayuse territory. They arrived just in time to pick up the pieces from the imminent disaster at Waiilatpu.

Immigrants brought many diseases, such as smallpox, measles, and cholera, for which the Indians had no natural immunity. A measles epidemic in 1847 decimated nearly half of the Cayuse population and nearly all of their children, while many of the whites survived. Since the Whitmans doctored both populations, some Cayuse suspected that Dr. Whitman was responsible. Perhaps this was a way to get land for the white settlers whom he had brought to the country.

Dr. Whitman and his wife were already familiar with the Cayuse tradition of holding medicine men responsible for their patient's recovery or death. Narcissa Whitman wrote to her parents, brothers, and sisters on May 3rd, 1837…

Last Saturday the War Chief died at W Walla he was a Cayuse & a relative of Umtippe was sick six days, employed the same W. W. Tewat [Cayuse medicine man] Umtippe sent for but he died in his hands. The same day Ye he kis kis a younger brother of Umtippe went to W W arrived about twilight & shot the Tewat dead. Thus they were avenged.

On Nov. 29th, 1847 a small band of Cayuse, along with a few Umatilla and Nez Perce allies, led a retaliation against the Whitmans to avenge the death of their family members. The Whitmans and some of their followers were killed, the buildings burned, and mission personnel taken captive.