Environmental heat exposure represents one of the most deadly natural hazards in the United States. Heat stroke is a life-threatening illness that affects all segments of society with few effective treatment strategies to mitigate the long-term debilitating consequences of this syndrome. Although the etiologies of heat stroke are not fully understood, the long-term sequelae are thought to be due to a systemic inflammatory response syndrome (SIRS) that ensues following heat-induced tissue injury. Endotoxin and cytokines have been implicated as key mediators of the heat-induced SIRS, based almost exclusively on correlative data that show high circulating concentrations of these substances in heat stroke patients and animal models. However, endotoxin and cytokine neutralization studies have not consistently supported this hypothesis indicating that the mechanisms of heat stroke morbidity / mortality remain poorly understood. This review discusses the current understanding of the role of endotoxin and cytokines in heat-induced SIRS. Insight is provided into genetic conditions that may predispose to heat stroke and potential therapeutic strategies that may be efficacious against the adverse consequences of this debilitating illness.