Prolonged strenuous exercise such as marathon running transiently increases the absolute and relative risk for sudden cardiac death. A 17-fold increase in the latter over resting baseline in previously sedentary middle-aged men is reduced due to cardioprotection from training in experienced marathon runners. Exertional rhabdomyolysis as a common occurrence during the race is accompanied by neutrophilia and elevated biomarkers of inflammation, including interleukin-6 and C-reactive protein. A hemostatic imbalance with prothrombotic effects includes in vivo platelet activation during the race. Suggesting a pathogenic role for these findings, plaque rupture due to atherothrombosis triggers acute exertional cardiac events, including sudden death, in low-risk runners as in high-risk patients such as those with diabetes mellitus. Strategies including prophylactic aspirin are considered to decrease the risk for acute cardiac events.