The consequence of myocardial ischemia is energetic stress, while reperfusion is accompanied by abrupt ionic shifts and considerable oxidative stress. Cells die by apoptotic and necrotic pathways. After the acute injury, the healing myocardium is subject to biomechanical stress and inflammation, which can trigger a smaller but more sustained wave of cell death, as well as changes in the metabolic and functional characteristics of surviving cells. The goal of cardioprotection is to prevent cell death during the acute injury as well as to modulate the detrimental processes that ensue during remodeling. This review will focus on acute injury, and the central premise is that mitochondria are the key determinant of cardiomyocyte fate.