This introductory chapter looks at psychedelic medicine from a cross-cultural perspective, illustrating the therapeutic and spiritual interpretations of their uses in many societies. The cross-cultural similarities in their use and interpretation reflect a biological foundation for their uses and effects. The chapter addresses some of the standard interpretations of these substances’ mechanisms of action in the serotonergic neurotransmitter system. The author’s analyses of the systemic effects of serotonergic transmission, and the interaction of the psychedelic medicines with serotonergic mechanisms, provide the basis for characterizing their effects as psychointegrative. Psychedelics produce a disinhibition of informational, emotional, and visual processes and stimulation of the integration of limbic system processes within the neocortex. This in effect integrates behavioral and emotional dynamics with the rational processes of the symbolic brain.