Background Missions were established in California in the eighteenth and nineteenth centuries to convert Native Americans to Christianity and enculturate them into a class of laborers for Californios (Spanish/Mexican settler). The concentration of large numbers of Native Americans at the Missions, along with the introduction of European diseases, led to serious disease problems. Medicinal supplies brought to California by the missionaries were limited in quantity. This situation resulted in an opportunity for the sharing of knowledge of medicinal plants between the Native Americans and the Mission priests. The purpose of this study is to examine the degree to which such sharing of knowledge took place and to understand factors that may have influenced the sharing of medicinal knowledge. The study also examines the sharing of medicinal knowledge between the Native Americans and the Californios following the demise of the California Missions. Methods Two methods were employed in the study: (1) a comparison of lists of medicinal plants used by various groups (e.g., Native American, Mission priests, Californios) prior to, during, and after the Mission period and (2) a close reading of diaries, reports, and books written by first-hand observers and modern authorities to find accounts of and identify factors influencing the exchange of medicinal information.