The physiological response to environmental toxicants and drugs is modulated by the thermoregulatory system. Environmental and body temperature can affect the entry of toxicants into the body through pulmonary, cutaneous, and gastrointestinal routes. Thermoregulation can ultimately influence the metabolic clearance of chemicals and their toxicity, including lethality. The thermoregulatory response following acute exposure to many toxic chemicals involves a regulated hypothermic response, characterized by activation of autonomic thermoeffectors to raise heat loss and a behavioral preference for cooler temperatures. Moderate hypothermia in rodents improves recovery and survival following toxic exposure. In relatively large mammals, including humans, the hypothermic response is minimal. Fever-like responses are often seen in humans and other large mammals exposed to many toxicants. Fever is also observed in rodents exposed to some toxicants provided that core temperature can be monitored without disturbing the animal (e.g., telemetry). Overall, the universal effects of temperature on chemical toxicity call for researchers to have a better understanding of how body and ambient temperature affect the physiological response to environmental toxicants.