The use of tobacco by South American Indians is deeply rooted in their culture and thought. From early pre-Columbian times to the present, tobacco has functioned as an important psychotropic drug for magico-religious, medicinal and recreational purposes. Native interest in tobacco centers on the nicotine alkaloid it contains. Data culled from about 1800 sources and pertaining to nearly 300 societies reveal that South American Indians employ six major and several minor means of nicotine application. There exists a close functional relationship between tobacco and shamanism. The empirical ethnographical data base of nicotine application is compared to the comprehensive literature of experimental clinical studies of tobacco and nicotine. Ritual tobacco use aims to achieve acute nicotine intoxication. The pharmacological effects of the alkaloid on the human body are shown to have informed shamanic therapeutic practices and beliefs. Closely associated with soil cultivation, tobacco use in the New World is much more recent than shamanism. Thus, it is not the drug that gave origin to shamanic religion but religion that informed the effects of the drug.