Cardiovascular diseases, such as stroke and myocardial infarction (MI) remain the major cause of death and disability worldwide. However, the mortality of MI has declined dramatically over the past several decades because of advances in medicines (thrombolytic agents, antiplatelet drugs, beta blockers, and angiotensin converting enzyme inhibitors) and approaches to restore tissue perfusion (percutaneous coronary intervention and cardiopulmonary bypass). Animal studies have been shown that these treatments have been effective in reducing acute myocardial ischemic injury and limiting MI size. The paradox is that the process of reperfusion can itself amplify cell injury and death, known as myocardial ischemia-reperfusion injury (I/R). Intensive research has uncovered several complex mechanisms of cardiomyocyte damage after reperfusion,and potential therapeutic targets for preventing I/R. Importantly, it is now recognized that excessive elevation of intracellular and mitochondrial Ca2+during reperfusion predisposes the cells to hypercontracture, proteolysis and mitochondrial failure and eventually to necrotic or apoptotic death. These enormous alterations in cytosolic Ca2+ levels are induced by the Ca2+ channels of the sarcolemma(L-Type Ca2+channels, sodium/calcium exchanger), the endoplasmic/ sarcoplasmic reticulum (SERCA ATPase) and ryanodine receptors, SOCE(store-operated calcium entry), lysosomes and others, which are modified by I/R injury. The overall goal of this review is to describe the different pathways that lead to I/R injury via Ca2+ overload, focus on recent discoveries and highlight prospects for therapeutic strategies for clinical benefit.