The impact of coronary artery disease on survival and quality of life is mainly due to cardiomyocyte death. Massive cardiomyocyte death occurs during acute myocardial infarction but emergency coronary recanalization is usually not able to prevent it. Laboratory research has demonstrated that a significant part of that cell death takes place during the first few minutes of reperfusion and that treatment aimed at disrupting the mechanisms responsible can reduce the size of the infarct. Those mechanisms include Ca2+ overload, mitochondrial permeabilization and cytoskeletal and membrane fragility (induced by the activation of proteases), all of which play critical roles. Moreover, cell death can propagate to adjacent cardiomyocytes via gap junctions. In addition, other myocardial and blood cells also contribute to both immediate and delayed cardiomyocyte death during reperfusion. Most forms of treatment developed to protect against reperfusion injury are still at the experimental stage, though some have been successfully tested in patients, such as atrial natriuretic peptide, inhibition of mitochondrial permeabilization and ischemic postconditioning. The possibility that myocardial salvage can be achieved by administering adjuvant treatment during coronary recanalization presents acute myocardial infarction patients with a new therapeutic option.