Heat stroke is a life-threatening illness that is characterized clinically by central nervous system dysfunction, including delirium, seizures, or coma and severe hyperthermia. Rapid cooling and support of multi-organ function are the most effective clinical treatments, but many patients experience permanent neurological impairments or death despite these efforts. The highest incidence of heat stroke deaths occurs in very young or elderly individuals during summer heat waves, with ∼ 200 deaths per year in the United States. Young, fit individuals may experience exertional heat stroke while performing strenuous physical activity in temperate or hot climates. Factors that predispose to heat stroke collapse include pre-existing illness, cardiovascular disease, drug use, and poor fitness level. For decades the magnitude of the hyperthermic response in heat stroke patients was considered the primary determinant of morbidity and mortality. However, recent clinical and experimental evidence suggests a complex interplay between heat cytotoxicity, coagulation, and the systemic inflammatory response syndrome (SIRS) that ensues following damage to the gut and other organs. Cytokines are immune modulators that have been implicated as adverse mediators of the SIRS, but recent data suggest a protective role for these proteins in the resolution of inflammation. Multi-organ system failure is the ultimate cause of mortality, and recent experimental data indicate that current clinical markers of heat stroke recovery may not adequately reflect heat stroke recovery in all cases. Currently heat stroke is a more preventable than treatable condition, and novel therapeutics are required to improve patient outcome.