Most toxicological and pharmacological studies are performed in laboratory animals maintained under comfortable environmental conditions. Yet, the exposure to environmental toxicants as well as many drugs can occur under stressful environmental conditions during rest or while exercising. The intake and biological efficacy of many toxicants is exacerbated by exposure to heat stress, which can occur in several ways. The increase in pulmonary ventilation during exposure to hot environments results in an increase in the uptake of airborne toxicants. Furthermore, the transcutaneous absorption of pesticides on the skin as well as drugs delivered by skin patches is increased during heat stress because of the combined elevation in skin blood flow coupled with moist skin from sweat. The thermoregulatory response to toxicant exposure, such as hypothermia in relatively small rodents and fever in humans, also modulates the physiological response to most chemical agents. This paper endeavors to review the issue of environmental heat stress and exercise and how they influence thermoregulatory and related pathophysiological responses to environmental toxicants, as well as exposure to drugs.