Marathon running poses a severe challenge to multiple regulatory systems and cellular homeostasis, especially when performed in hot environments without fluid replacement. During exercise in the heat, the ensuing dehydration causes hyperthermia and the synergistic effects of both stressors reduce cardiac output and blood flow to muscle, skin, brain and possibly splanchnic tissues. The drop in blood flow beyond the regulatory adjustment to concurrent increases in blood oxygen content leads to reductions in oxygen delivery, suppressed muscle aerobic energy turnover and greater reliance of the exercising muscles on anaerobic metabolism before fatigue. The accelerated hyperthermia-mediated fatigue during prolonged and maximal exercise is preceded by functional alterations in multiple bodily systems including the brain, heart and muscle. It is proposed that the impaired marathon running performance in warm environments is associated with a greater thermal, cardiovascular and metabolic strain, and perception of effort that prevents marathon runners from running at their personal record speed without inducing an accelerated regulatory dysfunction in multiple bodily systems.