St. Francis Cathedral, located east of the Santa Fe Plaza, is the fourth church constructed on this site. The first church, constructed in 1609, housed the statue of the Virgin Mary, La Conquistadora, believed to be the embodiment of Mary and is still displayed in the Cathedral today. The second mission church lasted only briefly and was destroyed during the Pueblo Revolt of the late 1600s. The Franciscan Friars in honor of Saint Francis of Assisi rebuilt the third church twenty years after the Spanish re-conquered Santa Fe and a small part of the third church still exists as an adobe chapel dedicated to "Our Lady La Conquistadora."

Father Lamy of France became Santa Fe's first bishop in 1852 and after viewing the humble accommodations, ordered a new Romanesque style church to be built. Unable to pay for the massive structure, including imported stained-glass windows from France, solely with tithes from the local Catholic community, Lamy also borrowed money from the local Jewish population. The church remained unchanged until the 1960s when the Cathedral underwent a structural reconditioning.

In 2005, Pope Benedict XVI elevated the Cathedral to Basilica status. In preparation for its 400th Anniversary the church underwent major improvements including repainting of original artwork and new church bells. St. Francis Cathedral, the heart of Santa Fe, is now a mixture of French, Spanish colonial, Mexican, and Native American influences reflecting the multicultural influences of the city.