Heat stroke is a life-threatening illness that affects all segments of society, including the young, aged, sick, and healthy. The recent high death toll in France (Dorozynski, 2003) and the death of high-profile athletes has increased public awareness of the adverse effects of heat injury. However, the etiology of the long-term consequences of this syndrome remains poorly understood such that preventive/treatment strategies are needed to mitigate its debilitating effects. Cytokines are important modulators of the acute phase response (APR) to stress, infection, and inflammation. Current data implicating cytokines in heat stroke responses are mainly from correlation studies showing elevated plasma levels in heat stroke patients and experimental animal models. Correlation data fall far short of revealing the mechanisms of cytokine actions such that additional research to determine the role of these endogenous substances in the heat stroke syndrome is required. Furthermore, cytokine determinations have occurred mainly at end-stage heat stroke, such that the role of these substances in progression and long-term recovery is poorly understood. Despite several studies implicating cytokines in heat stroke pathophysiology, few studies have examined the protective effect(s) of cytokine antagonism on the morbidity and mortality of heat stroke. This is particularly surprising since heat stroke responses resemble those observed in the endotoxemic syndrome, for which a role for endogenous cytokines has been strongly implicated. The implication of cytokines as mediators of endotoxemia and the presence of circulating endotoxin in heat stroke patients suggests that much knowledge can be gained from applying our current understanding of endotoxemic pathophysiology to the study of heat stroke. Heat shock proteins (HSPs) are highly conserved proteins that function as molecular chaperones for denatured proteins and reciprocally modulate cytokine production in response to stressful stimuli. HSPs have been shown repeatedly to confer protection in heat stroke and injury models. Interactions between HSPs and cytokines have received considerable attention in the literature within the last decade such that a complex pathway of interactions between cytokines, HSPs, and endotoxin is thought to be occurring in vivo in the orchestration of the APR to heat injury. These data suggest that much of the pathophysiologic changes observed with heat stroke are not a consequence of heat exposure, per se, but are representative of interactions among these three (and presumably additional) components of the innate immune response. This chapter will provide an overview of current knowledge regarding cytokine, HSP, and endotoxin interactions in heat stroke pathophysiology. Insight is provided into the potential therapeutic benefit of cytokine neutralization for mitigation of heat stroke morbidity and mortality based on our current understanding of their role in this syndrome.