Opioid drugs and endogenous opioid peptides exert profound effects on body temperature. The particular effect seen is dependent on species, ambient temperature, degree of restraint imposed on the subject, route of drug administration, and a number of other factors. A major determinant is the opioid receptor type with which the agonist forms a complex. Evidence is accumulating that opioid ligands and opioid receptors play a functional role in thermoregulation, even though the opioid system may not be tonically active. Although further studies are needed to fully define the role and the mechanisms involved, as well as the generality of the role in a variety of species, a reasonable working hypothesis is that mu receptors in the rat and the mouse are involved in responses that result in heat gain, while K receptor activation results in opposite responses. To a large extent, the mu receptors in the rat appear to be located primarily in the brain, while the K receptors are outside the brain and perhaps even outside of the central nervous system. At present there is no evidence of involvement of delta receptors in thermoregulation. A fuller understanding of the opioid system and its role in thermoregulation will have broad clinical implications, as well as provide insights into interactions among the several neurotransmitter systems involved in thermoregulatory control of body temperature.