Heatstroke is a life-threatening illness characterized by an elevated core body temperature (>40 degrees C) and dysfunction of central nervous system, which results in delirium, convulsions, or coma. Despite adequate hypothermia or other care-therapy, heatstroke is often fatal. On the basis of our knowledge of the pathophysiology on heatstroke, we hypothesized that heatstroke is a form of hyperthermia associated with the acute physiological alterations, the cytotoxicity of heat, systemic inflammatory response, oxidative damage and attenuated heat-shock response leading to a syndrome of multi-organ dysfunction. In view of above-mentioned situation, the physiological factors underlying heatstroke and the corresponding possible therapeutic strategies to avert the complications of this disorder would be summarized in this review so as to provide some therapeutic guidelines for heatstroke. Heatstroke is a very complicated process. Acute physiological alterations, such as low arterial hypotension, intracranial hypertension, cerebral hypoperfusion, cerebral ischemia, and increased intracellular metabolism rate, occurred while exposed to a high ambient temperature. Hyperpyrexia caused cytotoxicity, resulting the degradation and aggregation of extensive intracellular proteins, influencing the change of membrane stability and fluidity, damaging the transmembrane transport of protein and the function of surface receptor, and inducing different cytoskeletal changes. Heatstroke resembles sepsis in many aspects, and endotoxemia and cytokines may be implicated in its pathogenesis. The concentration of interleukin-6 was positively correlated with the severity of heatstroke. The excessive accumulation of cytotoxic free radicals and oxidative damage may occur in the brain tissues during the genesis and development of heatstroke. The circulatory shock and cerebral ischemia resultant from heatstroke correlated closely with the free radicals (especially free radicals of peroxide and superoxide), the peroxidation of lipids, and low activity of antioxidase in the brain. Heat-shock proteins (Hsps) played a critical role during the process obtaining thermotolerance, therefore, protected from stress-induce cellular damage. Host factors or physiologically limiting factors, for instance, aging, existing illness, dehydration, deep insomnia, lack of acclimation to heat, inadequate physical fitness, and certain genetic polymorphisms were associated with a low level of Hsps expression and might favor the progression from heat stress to heatstroke. Some measures, such as molecular chaperonines, anti-inflammatory agents, antioxidant agents, and modulators of Hsps would be good for the patients with heatstroke.