In the winter of 1842, Whitman went back east, returning the following summer with the first large wagon train of settlers across the Oregon Trail.

These new settlers encroached on the Cayuse Indians living near the Whitman Mission and were unsuccessful in their efforts to Christianize the tribe.

He studied medicine for two years with an experienced physician under the form of apprenticeship approved then, and received his degree from Fairfield Medical College in New York.

In 1835, Whitman traveled with the missionary Samuel Parker to present-day northwestern Montana and northern Idaho, to minister to bands of the Flathead and Nez Perce nations.

An additional cart drawn by two mules carried Milton Sublette, who had lost a leg a year earlier and walked on a "cork" one made by a friend.

Whitman farmed and provided medical care, while Narcissa set up a school for the Native American children.

More significantly, the influx of settlers in the territory brought new infectious diseases to the Indian Tribes, including a severe epidemic of measles in 1847.

The Native Americans' lack of immunity to Eurasian diseases resulted in high death rates, with children dying in large numbers.

Their despair at the deaths, especially of their children, led the Cayuse under Chief Tiloukaikt to kill the Whitmans in their home on November 29, 1847.

Warriors destroyed most of the buildings at Waiilatpu and killed twelve other white settlers in the community, kidnapping many children and forcibly marrying them in certain cases.

Historians have noted contemporary accounts of competition between the Protestant missionaries and Catholic priests, who had become established with Jesuit missions from Canada and St. Louis, Missouri, as contributing to the tensions.

The Roman Catholic priest John Baptiste Brouillet aided the survivors and helped bury the victims.

[6] Spalding later wrote a pamphlet stating forcefully that the Catholic priests, including Father Brouillet, had incited the Cayuse to massacre.

In 1901, Yale University historian Edward Gaylord Bourne convincingly disproved this revision of history, using the historical record to demonstrate that Whitman's trip back east was motivated by his desire to maintain the mission to convert the Native American tribes of the Northwest to Christianity and that he returned with settlers who were Protestant in order to promote (Protestant) Christianity.