This article reviews the attempts to understand the effects of psychedelic agents in human beings. The influence of paradigms as cognitive structures that both define and limit perception are reviewed. The uses of psychedelic substances are explored in terms of the effects of four major paradigms: 1) the Shamanic orientation, the most ancient and most subjective way of thinking about these substances, which holds that psychedelics are sacred. These metaphysical plants have spirit power, and are considered to be the “flesh of the Gods,” revered elements able to facilitate the carriage of an individual beyond the profane ordinary world into the ephemeral realms of the spirit. These divine plants are used in religious ceremonies, divination, and rites of membership and passage; 2) the Psychotomimetic (mimicking psychosis) view, which holds that these substances are drugs that produce hallucinations, and in this way induce a mental state resembling psychosis. This drug-induced state may serve as a laboratory model for mental illness; 3) the Psycholytic view, which holds that these drugs are psychodysleptic (mind dissolving), altering the relationship between the conscious and unconscious portions of the personality and producing a state of consciousness that can be useful in psychoanalytically oriented psychotherapy; and 4) the Psychedelic view, which regards psychedelic drugs as enabling peak or mystical experiences when administered in the proper dose, set and setting. These profoundly motivating subjective experiences are considered capable of producing lasting and positive changes in personality. Suggestions for a more encompassing view are provided, addressing the implications for training of clinician/experimenters and ethical principles for regulation of future research.