This article emphasizes significant recent advances regarding heat stress and its impact on exercise performance, adaptations, fluid electrolyte imbalances, and pathophysiology. During exercise-heat stress, the physiological burden of supporting high skin blood flow and high sweating rates can impose considerable cardiovascular strain and initiate a cascade of pathophysiological events leading to heat stroke. We examine the association between heat stress, particularly high skin temperature, on diminishing cardiovascular/aerobic reserves as well as increasing relative intensity and perceptual cues that degrade aerobic exercise performance. We discuss novel systemic (heat acclimation) and cellular (acquired thermal tolerance) adaptations that improve performance in hot and temperate environments and protect organs from heat stroke as well as other dissimilar stresses. We delineate how heat stroke evolves from gut underperfusion/ischemia causing endotoxin release or the release of mitochondrial DNA fragments in response to cell necrosis, to mediate a systemic inflammatory syndrome inducing coagulopathies, immune dysfunction, cytokine modulation, and multiorgan damage and failure. We discuss how an inflammatory response that induces simultaneous fever and/or prior exposure to a pathogen (e.g., viral infection) that deactivates molecular protective mechanisms interacts synergistically with the hyperthermia of exercise to perhaps explain heat stroke cases reported in low-risk populations performing routine activities. Importantly, we question the "traditional" notion that high core temperature is the critical mediator of exercise performance degradation and heat stroke. Published 2011. This article is a U.S. Government work and is in the public domain in the USA.