The missionaries at first preached from what came to be known as Pulpit Rock. The rock was near a spring, rich soil, and abundant timber. Adjacent to the rock the missionaries constructed several log buildings, including a dwelling house; three more structures, one used as a school; and outbuildings. Three years later a Catholic mission opened close by. The Methodist efforts at the Dalles failed because of the disinterest of the local Indians in Christianity; however, the mission served as a major stopping place at which wagon trains transferred to rafts to continue downriver. By the time many pioneers reached the mission, many were ill and half-starving as they faced the last great barrier of the Oregon Trail – the Cascade Mountains. Because of the steep cliffs that fell straight to the water’s edge, wagons either had to be abandoned or disassembled and loaded onto rafts and floated down to Fort Vancouver or to the Willamette Valley.

However, in 1845, the Barlow Road began to built, and when it was complete the following year, it provided a choice of traveling overland into the valley. Most of the emigrants shifted to the new road and the Dalles declined in importance. In 1847, the Methodist Mission Society sold The Dalles Mission, its last active post in the Oregon country, to the American Board of Commissioners for Foreign Missions. Dr. Marcus Whitman, representing the board, placed his nephew, Perrin B. Whitman, in charge of The Dalles Mission, but he departed in December, the month after the Waiilatpu Massacre. That same month, volunteer troops arrived from Fort Vancouver and occupied the site.

Protecting the settlers from the troubles that led to the Cayuse War in 1848, the soldiers initially occupied the abandoned Methodist mission buildings before building a temporary stockade. The post was unofficially called Fort Lee at this time.

In 1850, two rifle companies from Fort Vancouver came to establish a supply depot known as Camp Drum, and the post became official. Later, it was renamed Fort Dalles. By 1852, a town had grown up around the post, which had become the headquarters for central and eastern Oregon, protecting the area settlers and the Oregon Trail from Indian attacks.

Resenting the invasion of settlers and miners into the region that followed the cession of a large part of their lands to the U.S. Government in 1855, the Yakama and allied tribes, spurred by the Yakama Chief Kamiakin, disavowed the treaties and retaliated. Colonel George Wright's campaign, with a force of Infantry Regulars, brought the war to an end in 1856.