On June 27, 1776, Father Francisco Palou and Lieutenant José Joaquin Moraga, accompanied by sixteen Spanish soldiers, led a small party of Spanish-American settlers to the shores of San Francisco Bay. Although the settlers had arrived well in advance of their supply ship, they set about establishing a mission and town. Palou chose a site on a little inlet known as Laguna de Nuestra Señora de los Dolores for the mission, which was named Misión San Francisco de Asís (Mission of Saint Francis of Assisi). The town, established nearby, was named Yerba Buena. As time went by the town took the name Saint Francis, while the mission more popularly became known as Dolores. A presidio (military fort) was also established in the area.

The first services were conducted on the site on June 29, 1776. Permanent mission buildings were completed by September 1, and the mission was dedicated on October 9, 1776.

The mission soon became popular with the Native Americans of the area, who eagerly accepted the food and protection provided by the padres. But, while the mission had little trouble attracting "members," it had a very difficult time keeping them. The Native Americans found the religious teachings of the padres difficult to understand. In addition, they were easily distracted by the less-structured life offered by the nearby fort and settlement. And, those Native Americans who did choose to remain at the mission faced the very real threats of measles and other European-borne diseases. To make matters even worse, good agricultural land was difficult to come by, due to the steady growth of the nearby town to the north and expansive mud flats to the south. Despite all these problems the mission managed to persevere.

Although the mission remained in operation for some sixty years, its infrastructure diminished greatly. Land reforms instituted by the Mexican government took away much of the agricultural land the mission owned. Today all that remains of the original mission is its church. Now the oldest building in San Francisco, Mission Dolores (as it is now called), withstood the San Franciso Earthquake of 1906 with barely a crack in its thick walls. Located in the present-day Mission District, it is a popular tourist attraction.

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