A wealth of data indicates that performing regular exercise is an important lifestyle modification to prevent cardiovascular disease. Although not fully understood, the cardioprotection by regular exercise may be exerted synergistically through improvement in many risk factors associated with cardiovascular disease. Just as important are the direct effects of exercise on the myocardium, resulting in cardioprotection against ischemia-reperfusion (I-R) injury. Cardioprotective countermeasures against myocardial I-R injury may include the development of collateral coronary arteries, induction of myocardial heat shock proteins, and improved cardiac antioxidant capacity. Improving our understanding of the molecular basis for exercise-induced cardioprotection will play an important role in developing optimal exercise interventions to protect the heart from ischemic injury.