Myocardial ischemia-reperfusion (IR) injury is the primary contributor to the morbidity and mortality associated with coronary artery disease. Depending on the duration of ischemia, three levels of IR-induced cardiac injury have been identified. The cellular events leading to IR-induced cellular injury are complex, but the key elements include IR-induced radical production, cellular disturbances in calcium homeostasis, and activation of cellular proteases. Moreover, growing evidence indicates that mitochondrial injury plays a major role in IR-induced injury, because mitochondria seem to be the final arbitrators of IR-induced cell death and determine whether the myocyte will die from necrosis or apoptosis. This review will provide a brief summary of our current understanding of the cellular events that contribute to IR-induced cardiac injury and cell death. Further, we will briefly introduce the concept of cardioprotection and outline several successful approaches that can induce a cardioprotective phenotype. Finally, in hopes of stimulating future research, this review will also identify important gaps in our knowledge of IR-induced myocardial injury.