Heat stroke is defined as a condition in which body temperature is elevated to such a level that it becomes a noxious agent causing body tissue dysfunction and damage with a characteristic multi-organ clinical and pathological syndrome. Marked hyperthermia, usually above 40.5 °C and associated encephalopathy, occurs after thermoregulation is subordinated to circulatory and metabolic demands and to the associated systemic inflammatory reaction. Exertional heat stroke is a function of both intrinsic and extrinsic modulators. Intrinsic modulators like genetics, fitness, acclimatization, illness, medications, and sleep quality can alter individual risk and outcomes, while extrinsic modulators like exercise intensity and duration, clothing and equipment, ambient temperature, relative humidity, and solar radiation can affect the group risk and outcomes. This review integrates the current theoretical and accepted knowledge of physiological alterations into one model that depicts a common pathway from heat stress to heat stroke.