The Spaldings and their fellow missionaries were among the earliest Americans to travel across the western plains, through the Rocky Mountains and into the lands of the Pacific Northwest to their religious missions in what would become the states of Idaho and Washington.

Their missionary party of five, including Marcus Whitman and his wife Narcissa and William H. Gray, joined with a group of fur traders to create the first wagon train along the Oregon Trail.

He left, without graduation, upon his appointment in 1836 by the Boston-based American Board of Commissioners for Foreign Missions (ABCFM) as a missionary to the Nez Perce Indians of Idaho.

The Spaldings searched for a missionary station through the American Board of Commissioners for Foreign Missions, and were initially assigned to the Osage in Missouri.

In July 1836, while the company paused at the Rendezvous in the Wind River Mountains of Wyoming, Spalding wrote a letter to a fellow minister and newspaper editor about the journey west.

The letter, preserved in a transcript by the "Library of Western Fur Trade Historical Source Documents", provides one of the earliest first hand accounts about the route west and conditions found during this journey across the North American continent.

He developed an appropriate written script for the Nez Perce language, and translated parts of the Bible, including the entire book of Matthew, for the use of his congregation.

Eliza Spalding was very well liked by the Nez Perce peoples, whose women often followed her around her home wanting to see how the "white woman" cooked, cleaned, dressed, and cared for her children.

Amid criticism by Whitman and others in the region, Spalding was dismissed by the American Board in 1842, although he never left his mission or stopped his missionary work.

On November 29, 1847, Marcus and Narcissa Whitman and twelve male emigrants (ten adult men and two boys of 15 and 18) of their mission at Waiilatpu, Washington were killed at the hands of several Cayuse.

The natives blamed them for introducing deadly diseases, including the measles, as the tribe had experienced a recent epidemic and a number of children had died.

Two days later en route to the Whitmans', Spalding learned of the murders from Catholic priest John Baptist Brouillet, who had heard what had happened and had gone to the mission to assist with the burials.

[5] Spalding was able to rejoin his family at Lapwai, Idaho| where they had found shelter with William Craig and the Nez Perce, who held the Spaulding party as "hostages for peace".

[7] Concerned over continuing violence between Native Americans and settlers in the area, and against Spalding's wishes, the ABCFM decided to make the abandonment of the mission permanent.

[8] The Spaldings built a small home in the area, while Eliza became the first teacher at Tualatin Academy, which eventually grew into Pacific University.

He felt strongly enough about the latter that, in October 1870, he took a steamship to San Francisco, then rode the new transcontinental railroad to Chicago, then to his birthplace, to New York City, Boston, and Washington, D.C.

Under the auspices of the Presbyterian Board of Missions, Spalding also continued missionary work with native tribes in northwestern Idaho and northeastern Washington territories.

[10] The Presbyterian Historical Society in Philadelphia, Pennsylvania, has a collection of eight original letters of Henry and Eliza Spalding to family members.