Cardiovascular disease (CVD) is potentiated by risk factors including physical inactivity and remains a leading cause of morbidity and mortality. Although regular physical activity does not reverse atherosclerotic coronary disease, precursory exercise improves clinical outcomes in those experiencing life-threatening CVD events. Exercise preconditioning describes the cardioprotective phenotype whereby even a few exercise bouts confer short-term multifaceted protection against acute myocardial infarction. First described decades ago in animal investigations, cardioprotective mechanisms responsible for exercise preconditioning have been identified through reductionist preclinical studies, including the upregulation of endogenous antioxidant enzymes, improved calcium handling, and enhanced bioenergetic regulation during a supply-demand mismatch. Until recently, translation of this research was only inferred from clinically-directed animal models of exercise involving ischemia-reperfusion injury, and reinforced by the gene products of exercise preconditioning that are common to mammalian species. However, recent clinical investigations confirm that exercise preconditions the human heart. This discovery means that simply the initiation of a remedial exercise regimen in those with abnormal CVD risk factor profiles will provide immediate cardioprotective benefits and improved clinical outcomes following acute cardiac events. In conclusion, the prophylactic biochemical adaptations to aerobic exercise are complemented by the long-term adaptive benefits of vascular and architectural remodeling in those who adopt a physically active lifestyle.