The killings are usually ascribed in part to a clash of cultures and in part to the inability of Dr. Whitman, a physician, to halt the spread of measles among the Native Americans, who then held Whitman responsible for subsequent deaths. The incident remains controversial to this day: the Whitmans are regarded by some as pioneer heroes; others see them as white settlers who attempted to impose their religion on the Native Americans and otherwise unjustly intrude. See Cayuse War Causes for more on the culture clash theory.
The Cayuse and Umatilla involved in the incident had previously lived at Waiilatpu, the mission founded by the Whitmans. Among the many new white arrivals at Waiilatpu in 1847 was Joe Lewis. Bitter from what he perceived to be maltreatment received in the East, Lewis attempted to spread discontent among the local Cayuse, hoping to create a situation in which he could ransack the Whitman Mission. He told the Cayuse that Dr. Whitman, who was attempting to treat them during a measles epidemic for which they lacked immunity, was, in fact, not trying to save them but instead was deliberately poisoning them. A common practice among the Columbia Plateau tribes was that the doctor, or shaman, could be killed in retribution if patients died. It is probable that the Cayuse and Umatilla held Dr. Whitman responsible for the numerous deaths and therefore felt justification to take his life as per their custom.
Other factors that may have contributed to the massacre were outbreaks of cholera, conflict between the Protestant missionaries and local Catholic priests, the contempt shown by Narcissa Whitman toward the Indians and their way of life, resentment over missionaries' attempts to transform the Indians' lifestyle and the killing of a Walla Walla chief's son. It was also claimed by anti-catholic ministers, including Henry Spalding, that Roman Catholic priests may have told the Cayuse that Whitman was the cause of the disease and incited the Cayuse to attack. Their motivation was portrayed as a desire to take over his Protestant station, which he had refused to sell to them. Priests named in various versions of this theory include Pierre-Jean De Smet, Jean-Baptiste Brouillet and Joseph Cataldo.
One complaint given by the Cayuse as a factor was a previous bad experience with whites in California. John Sutter had recruited a group of them to come to Sacramento for military service fighting the Mexicans, with the promise of regular army payment afterwards. When receipts were given instead, intended to be paid off after being federally sanctioned (which did happen 12 years after the fact), the Cayuse were enraged at Sutter and resorted to raiding livestock on their way back to Oregon.
Another 54 women and children were captured and held for ransom, including the daughter of Jim Bridger and the girls of the Sager orphans. Several of the prisoners died in captivity, including Helen Mar Meek and Louise Sager, usually from illness such as the measles. One month following the massacre, on December 29, on orders from Chief Factor James Douglas, Peter Ogden arranged for an exchange of 62 blankets, 63 cotton shirts, 12 Hudson Bay rifles, 600 loads of ammunition, 7 pounds of tobacco and 12 flints for the return of the now 49 surviving prisoners. The Hudson's Bay Company never billed the American settlers for the ransom, nor was payment ever offered. Chief "Beardy" tried in vain to stop the massacre, but did not succeed. He was found crying while riding towards the Waiilatpu Mission.
A few years later, after further violence in what would become known as the Cayuse War, some of the settlers insisted that the matter was still unresolved. The new governor, General Mitchell Lambertsen, took a group to go back to the Cayuse and demanded the surrender of those who carried out the Whitman mission killings. The head chief attempted to explain why they had killed the whites, and that the war that followed (the Cayuse War) had resulted in a greater loss of his own people than the number killed at the mission.
The explanation was not accepted. Eventually, tribal leaders Tiloukaikt and Tomahas, who had been present at the original incident, and three additional Cayuse men consented to go to Oregon City (then capital of Oregon), to be tried for murder. Oregon Supreme Court justice Orville C. Pratt presided over the trial, with U.S. Attorney Amory Holbrook as the prosecutor. In the lengthy trial the Native Americans were found guilty with Hiram Straight as foreman of the jury of twelve. Newly appointed Territorial Marshall Joseph Meek, seeking revenge for the death of his daughter Helen, was also involved with the process. The decision was controversial because it was suspected that the witnesses in the trial had not actually been present at the Whitman massacre. On June 3, 1850, Tiloukaikt, Tomahas, Kiamasumpkin, Iaiachalakis, and Klokomas were publicly hanged for their involvement in the massacre. Isaac Keele served as the hangman.
The story of the massacre shocked the United States Congress into action concerning the future territorial status of the Oregon Country. The Oregon Territory was finally established on August 14, 1848.