It has long been recognized that there are central nervous system mechanisms that can strikingly alter the perception of noxious stimuli. Indeed, recent theoretical treatments of pain have often given explicit recognition to this notion although little physiological detail has been available to support it [76, 78, 83]. The intent of this review is to examine and synthesize the extensive progress that has been made in the last few years describing the anatomical, physiological and neurohumoral substrates of neural systems which modulate pain perception. Particular progress has been made in elucidating a neural system which can be activated by electrical stimulation of certain brain stem structures as well as by the narcotic analgesic drugs. For this reason, considerable emphasis will be placed on explaining its mechanisms. However, we will also review some recent evidence showing that other neural systems as well participate importantly in the modulation of pain.