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. Results: A comparison of the lists of medicinal plants use by various groups indicated that only a small percentage of medicinal plants were shared by two or more groups. For example, none of the 265 taxa of species used by the Native Americans in pre-Mission times were imported into Spain for medicinal use and only 16 taxa were reported to have been used at the Missions. A larger sharing of information of medicinal plants took place in the post-Mission period when Native Americans were dispersed from the Missions and worked as laborers on the ranches of the Californios. Conclusions: Sharing of information concerning medicinal plants did occur during the Mission period, but the number of documented species was limited. A number of possible factors discouraged this exchange. These include (1) imbalance of power between the priests and the Native Americans, (2) suppression of indigenous knowledge and medical practices by the Mission priests, (3) language barriers, (4) reduction of availability of medicinal herbs around the Mission due to introduced agricultural practices, (5) desire to protect knowledge of medicinal herbs by Native American shaman, (6) administrative structure at the Missions which left little time for direct interaction between the priests and individual Native Americans, (7) loss of knowledge of herbal medicine by the Native Americans over time at the Missions, and (8) limited transportation opportunities for reciprocal the shipment of medicinal plants between California and Spain. Three possible factors were identified that contributed to a greater sharing of information between the Native Americans and the Californios in the post-Mission period. These were (1) more one-to-one interactions between the Californios and the Native Americans, (2) many of the Californios were mestizos whose mothers or grandmothers were Native Americans, and (3) lack of pressure on the part of the Californios to suppress Native American beliefs and medicinal practices. [ABSTRACT FROM AUTHOR]