This symposium focuses on exertional heatstroke, with emphasis on predisposing factors, clinical observations, diagnosis, treatment and recovery. The serious challenge to cardiovascular stability presented by exercise hyperthermia and some aspects of regulatory failure was reviewed in the introduction. The intent of this review, to understand how heat stress is translated into heat strain at the cellular level, is not to downplay the seriousness of the systemic condition. If we are successful, this may stimulate further interest on the impact of heat on the cell as a model for other factors which alter membrane integrity and permeability, lead to new experimental paradigms, and improve the diagnosis and treatment of other disorders such as toxic, hypovolemic, or ischemic shock. This review may also stimulate interesting research regarding more subtle threats to homeostasis such as chronic exercise, hypohydration and thirst, ion imbalance, and sleep deprivation. Since the original article on heat stroke pathophysiology was published (39), we have discussed the relationship of this concept to carbohydrate metabolism (40), thirst (41), and the cellular aspects of heat illness treatment (99). This article will attempt to integrate and extend some of those ideas.