Myocardial ischemia-reperfusion (I-R) injury is a major contributor to the morbidity and mortality associated with coronary artery disease. The incidence of I-R events is greatest in older persons, and studies also indicate that the magnitude of myocardial I-R injury is greater in senescent individuals compared to younger adults. Regular exercise has been confirmed as a pragmatic countermeasure to protect against I-R-induced cardiac injury. Specifically, endurance exercise has been proven to provide cardioprotection against an I-R insult in both young and old animals. Proposed mechanisms to explain the cardioprotective effect of exercise include the induction of myocardial heat shock proteins (HSPs), improved cardiac antioxidant capacity, and/or elevation of other cardioprotective proteins. Of these potential mechanisms, evidence indicates that elevated myocardial levels of heat shock proteins or antioxidants can provide myocardial protection against I-R injury. At present, which of these protective mechanisms is essential for exercise-induced cardioprotection remains unclear. Understanding the molecular basis for exercise-induced cardioprotection is important in developing exercise paradigms to protect the heart during an I-R insult.