Situated in the heart of San Francisco's historic Italian neighborhood, the Norman Gothic Church of Saint Francis of Assisi was dedicated as a parish church on 17 March 1860. The twin towers and walls survived the 1906 Earthquake and Fire, but the interior was gutted. The parish built a new church within the surviving walls and rededicated it on 2 March 1919.

Although this building is no longer a parish church, the National Conference of Catholic Bishops, responding to prodding from Archbishop William J. Levada, granted it the title of National Shrine of Saint Francis of Assisi in 1999.

Among the assets of the shrine are a 1926 pipe organ from the Schoenstein Organ Company and relics of Saint Francis of Assisi, Saint Clare of Assisi, and Saint Anthony of Padua.