The narrative is based on two historical figures of the late 19th century, Jean-Baptiste Lamy and Joseph Projectus Machebeuf, and rather than any one singular plot, is the stylized re-telling of their lives serving as Roman Catholic clergy in New Mexico. The narrative has frequent digressions, either in terms of stories related to the pair (including the story of the Our Lady of Guadalupe and the murder of an oppressive Spanish priest at Acoma Pueblo) or through their recollections. The narration is in third-person omniscient style. Cather includes many fictionalized accounts of actual historical figures, including Kit Carson, Manuel Antonio Chaves and Pope Gregory XVI.

In the prologue, Bishop Ferrand, an Irish bishop who works in the New World, solicits three cardinals at Rome to pick his candidate for the newly created diocese of New Mexico (which has recently passed into American hands). Bishop Ferrand is successful in getting his candidate, the Auvergnat Jean-Marie Latour, recommended by the cardinals over the recommendation of the Bishop of Durango (under whose territory New Mexico had previously fallen). One of the cardinals, a Spaniard named Allende, alludes to a painting by El Greco taken from his family by a missionary to the New World and lost, and asks for the new Bishop to search for it.