Psychologists may soon be entering into the practice of pharmacologic treatment of mental illness. Although there has been some investigation of biologic differences in drug response among various ethnic and racial groups, very little attention has been paid to the nonbiologic differences. Cultural definitions of health, healing, and illness and specific cultural practices are likely to have a significant impact on various aspects of treatment, compliance, and interaction effects. This article addresses the issue of culture and the impact of cultural practices on the use of psychotropic medications with the Lakota (Sioux) people of the Northern Plains. Specific examples of traditional Lakota ceremonies and their potential interactions with psychotropic medications are presented with recommendations to prescribers for handling these situations in a culturally responsive manner. Emphasis is placed on creating collaborative relationships between prescribers and traditional spiritual healers in the care of Native American clients. Recommendations for future research are discussed.