Most Orinocoan ethnic groups, including the Cuiva and the Piaroa, use yopo, a hallucinogenic snuff derived from the seeds of the Anadenanthera peregrina tree. This study contrasts Piaroa and Cuiva attitudes toward and uses of yopo in light of ongoing processes of social change. We do not believe that these sociocultural forces will lead to a phasing out of yopo in Piaroa and Cuiva life. However, we demonstrate how, in nearby communities, a combination of historical and ethical contingencies lead to very different patterns and understanding of drug use. Yopo is strongly associated with the performance of narratives central to each ethnic group’s cosmology and identity. Cuiva yopo consumption is also a means of resisting persecution and asserting the right to a just reality. Piaroa attitudes towards yopo are affected by the interplay of shamanic ethical principles and missionary activity, and are sometimes paradoxical: yopo is the reason for harm and the means of salvation; required by shamans to create the future and yet regarded by many laypeople as a relic of the past. We identify persecution, local responses to missionary activity, and shamanic ethics as key factors affecting the evolution of hallucinogen use by Amazonian ethnic groups.