Microarray analysis of gene expression at the level of RNA has generated new insights into the relationship between cellular responses to acute heat shock in vitro, exercise, and exertional heat illness. Here we discuss the systemic physiology of exertional hyperthermia and exertional heat illness, and compare the results of several recent microarray studies performed in vitro on human cells subjected to heat shock and in vivo on samples obtained from subjects performing exercise or suffering from exertional heat injury. From these comparisons, a concept of overlapping component responses emerges. Namely, some of the gene expression changes observed in peripheral blood mononuclear cells during exertional heat injury can be accounted for by normal cellular responses to heat, exercise, or both; others appear to be specific to the disease state itself. If confirmed in future studies, these component responses might provide a better understanding of adaptive and pathological responses to exercise and exercise-induced hyperthermia, help find new ways of identifying individuals at risk for exertional heat illness, and perhaps even help find rational molecular targets for therapeutic intervention.