Marcus Whitman was born in 1802 in Federal Hollow, New York, and grew up in Rushville, New York. Although deeply religious, he was unable to afford training as a minister. He instead earned a degree from Fairfield Medical College in 1832, and applied to be a medical missionary for the American Board of Commissioners for Foreign Missions (ABCFM). In 1835, he and Samuel Parker traveled to the Pacific Northwest to explore the feasibility of establishing a mission to convert Native people to Protestant Christianity.

In February 1836, Whitman married Narcissa Prentiss of Angelica, New York. Narcissa Whitman had been deeply religious since childhood and desired to become a Presbyterian missionary, but had previously been rejected by the ABCFM; her marriage to Marcus Whitman enabled her to become a missionary. That year, the couple traveled westward with Henry Harmon Spalding, Eliza Hart Spalding, and William H. Gray. The Whitmans established a mission at Waiilatpu, located in the lands of the Cayuse people near Walla Walla, in what would later be Washington State, while the Spaldings established a separate mission at Lapwai in what would later be Idaho. In March 1837, Narcissa Whitman gave birth to a daughter, Alice Clarissa Whitman, who lived only two years; she drowned in 1839.

In 1838, additional missionaries arrived to assist Whitman's efforts to convert the region's Native peoples, including Elkanah Walker and Asa Smith. There were conflicts among the Whitmans and other missionaries, and by the 1840s, the Whitmans' efforts to convert Native people were proving largely unsuccessful. After receiving multiple letters from Asa Smith that were critical of the missionaries, the ABCFM announced in 1842 that it would recall Smith and Gray for reassignment and dismiss Spalding from missionary work, and that Whitman was to close the mission at Waiilatpu and relocate to Elkanah Walker's mission further north. In response, Marcus Whitman traveled east to meet with the ABCFM in person, and convinced them to rescind their orders. In 1843, he returned to the Pacific Northwest, helping guide a large wagon train of Euro-American emigrants to the Oregon Territory.

Relations between the Whitmans and the Cayuse were frequently confrontational. The Whitmans disapproved of Cayuse cultural practices, and there were misunderstandings relating to Euro-American cultural norms such as privacy. Because the Whitmans had built a sizeable mission and residence on Cayuse land, the Cayuse believed the Whitmans were obligated to distribute their goods to them, which the Whitmans interpreted as selfishness and ingratitude. In addition, as time went on, Marcus Whitman became more involved with assisting the increasing number of Euro-American emigrants coming to the region, while Narcissa Whitman became more focused on helping to raise and educate children of Euro-American emigrants and of fur trappers.

Tensions came to a head in 1847, when a measles epidemic hit the Cayuse people. The Cayuse believed that healers, such as Marcus Whitman, possessed powers and were thus responsible for the deaths of anyone in their care. Contemporary sources also indicate that there were rumors among the Cayuse that Whitman was deliberately poisoning them. On November 29, 1847, a group of Cayuse killed the Whitmans and eleven or twelve other Euro-Americans at the mission, and took the rest of those present hostage; the hostages were freed a month later, when Peter Skene Ogden of the Hudson's Bay Company paid ransom for them.

The killings, dubbed "the Whitman Massacre" by Euro-Americans, triggered a war between the Cayuse and Euro-American emigrants. In 1850, the Cayuse surrendered five men: Telokite, Tomahas, Isiaasheluckas, Clokomas, and Kiamasumkin. These five were then brought to Oregon City, Oregon, where they were tried and executed for the killings. The United States subsequently seized the Cayuse's land in 1855, and forced them to live on the Umatilla Reservation.

Sources: "Marcus Whitman (1802-1847)," by G. Thomas Edwards, Oregon Encyclopedia, https://www.oregonencyclopedia.org/articles/whitman_marcus/#.YnqytOjMIuU; "Narcissa Whitman (1808-1847)," by G. Thomas Edwards, Oregon Encyclopedia, https://www.oregonencyclopedia.org/articles/whitman_narcissa_1808_1847_/#.Ynqov-jMIuU; "Whitman Murders," by Cameron Addis, Oregon Encyclopedia, https://www.oregonencyclopedia.org/articles/whitman_massacre/#.YnqovejMIuU; "Whitman Murders Trial," by Ronald B. Lansing, Oregon Encyclopedia, https://www.oregonencyclopedia.org/articles/whitman_massacre_trial/#.Ynqxy-jMIuU; Confederated Tribes of the Umatilla Indian Reservation, “A Brief History of CTUIR,” https://ctuir.org/about/brief-history-of-ctuir/; Drury, Clifford M., "Marcus and Narcissa Whitman and the Opening of Old Oregon," 1973.