A fascinating class of psychoactive substances possessing a long and mysterious history of human use are the classic hallucinogens. Forming a vital component of prehistorical and aboriginal culture and belief systems, hallucinogens were ultimately condemned and repressed by evolving civilizations, only to the “rediscovered” in the 20th century. Of compelling interest to anthropologists, ethnobotanists, pharmacologists, medical scientists, and mental health clinicians, their use was diverted to the general culture, particularly among youth during the politically tumultuous 1960s: it was determined to be the cause of a period of cultural upheaval associated with a perceived public health crisis. After decades of quiescence, however, the careful examination of hallucinogens under rigorous and approved research conditions has resumed. This chapter will explore the historical background, neuropharmacology, cultural use, risks of adverse events/addiction, recent renaissance of controlled research, and models for optimal use and implications for the future.