The primary character is a bishop, Jean Marie Latour, who travels with his friend and vicar Joseph Vaillant from Sandusky, Ohio to New Mexico to take charge of the newly established diocese of New Mexico, which has only just become a territory of the United States. The names given to the main proponents reflect their characters. Vaillant, valiant, is fearless in his promulgation of the faith, whereas Latour, the tower, is more intellectual and reserved than his comrade.
At the time of his departure, Cincinnati is the end of the railway line west, so Latour must travel by riverboat to the Gulf of Mexico, and thence overland to New Mexico, a journey which takes an entire year. He spends the rest of his life establishing the Roman Catholic church in New Mexico, where he dies in old age.
The novel portrays two well-meaning and devout French priests who encounter a well-entrenched Spanish-Mexican clergy that they are sent to supplant after the United States has acquired New Mexico in the Mexican–American War. As a result of the U.S. victory, the dioceses of the new state have been remapped by the Vatican to reflect the new national borders.
Several of these entrenched priests are depicted as examples of greed, avarice, and gluttony, while others live simple, abstemious lives among the Native Americans. Cather portrays the Hopi and Navajo sympathetically, and her characters express the near futility of overlaying their religion on a millennia-old native culture.