The prevalence of coronary artery disease renders myocardial ischemia a leading cause of morbidity and mortality. Both cardiac bypass operations and cardiac transplantation cause myocardial ischemia and reperfusion injury. Intracellular calcium transport and regulation are of paramount importance in both normal and pathologic myocardial states. Calcium regulation is integral to nearly every myocyte function, from early development to senescence. Normal intracellular calcium-mediated excitation-contraction coupling and abnormal patterns of calcium regulation leading to systolic/diastolic dysfunction are now therapeutically accessible to the cardiac surgeon. Additionally, altered Ca2+ transport protein gene expression is a mechanism of myocardial dysfunction. Therapeutic strategies involve receptor-mediated transduction of signals to intracellular metabolic sites. Evidence implicates protein kinase C as well as a potential therapeutic role for Ca2+. The potential for pharmacologic access to this protective state has abundant clinical appeal. The protective state (cardiac "preconditioning") is transient but is amenable as therapy against operation-related ischemic events.