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.
The Provisional Legislature of Oregon and Governor George Abernethy called for "immediate and prompt action," and authorized the raising of companies of volunteers to go to war, if necessary against, the Cayuse Tribe. A fifty person unit of volunteers was raised immediately and dispatched to The Dalles under the command of Henry A. G. Lee. Called the Oregon Rifles, they were formed on December 8 1847, and then gathered at Fort Vancouver on December 10, where they purchased supplies from the Hudson’s Bay Company (HBC) post. The HBC would not extend credit to the Provisional Government, therefore the volunteer soldiers each pledged their individual credit to purchase supplies with the expectation that the government would repay them at a later time. The group was to protect the Methodist’s Wascopam Mission at The Dalles and prevent any hostile forces from reaching the Willamette Valley. In addition, the Governor appointed a peace commission, consisting of Joel Palmer, Lee, and Robert Newell.
The Oregon Rifles marched to The Dalles, arriving on December 21. Upon arriving there, they drove off a band of Native Americans, but not before the Natives stole 300 head of cattle. There the troops built a stockade and named the post Fort Lee for the commander, though the small fortification was also called Fort Wascopam. In January 1848, a force of over 500 militiamen led by Colonel Cornelius Gilliam (who did not approve of the peace commission) marched against the Cayuse and other native inhabitants of central Oregon. These troops arrived at Fort Lee in February, and with a larger force, the militia forces pressed east towards the Whitman Mission. By March 4 the forces reached the mission after a battle at Sand Hollows. After reaching the mission, Col. Gilliam set out to return to The Dalles with a small force to supply that settlement, before continuing to Oregon City to report to the governor. However, on the journey Gilliam was accidentally killed in camp, with Lee then continuing on to Oregon City with Gilliam’s body. Lee was then promoted to Colonel, but upon returning to the front resigned as colonel, but remained as an officer, after learning the troops had elected Lieutenant-Colonel James Waters as colonel to lead the troops.
These militia forces were later supported by the United States Army. Some Cayuse initially refused to make peace and raided isolated settlements while others, considered friendly to the settlers, tried to work with the peace commission. The militia forces, eager for action, provoked both friendly and hostile Indians. Many Cayuse resisted, but they were unable to put up an effective opposition to the firepower of their opponents, and were driven into hiding in the Blue Mountains.
In 1850, the tribe handed over five members (Tilaukaikt, Tomahas, Klokamas, Isaiachalkis, and Kimasumpkin) to be tried for the murder of the Whitmans. All five Cayuse were convicted by a military commission and hanged on 3 June1850. The hanging was conducted by U.S. Marshal Joseph L. Meek. Kimasumpkin's final statement:
I was up the river at the time of the massacre, and did not arrive until next day. I was riding on horse back; a white woman came running from the house, she held out her hands and told me not to kill her. I put my hand upon her hand and told her not to be afraid. There were plenty of Indians all about. She with the other women and children went to Wallawalla to Mr. Ogden's. I was not present at the murder nor was I any way concerned in it. - I am innocent - it hurts me to talk about dying for nothing. Our chief told me to come down and tell all about it. - Those who committed the murder are killed and dead. The priest say I must die tomorrow, if they kill me I am innocent… My Young Chief told me I was to come here to tell what I know concerning the murderers. I did not come as one of the murderers, for I am innocent. - I never made any declaration to any one that I was guilty. This is the last time that I may speak.
This did not end the conflict, though, and sporadic bloodshed continued for another five years until the Cayuse were finally defeated in 1855.
The war had significant long-term consequences for the region. It opened the Cayuse territories to white settlement, but wrecked relations between whites and the native tribes and set the scene for a series of fresh wars over the following forty years.