Despite better outcomes with early coronary artery reperfusion for the treatment of acute ST-elevation myocardial infarction (MI), morbidity and mortality from acute myocardial infarction (AMI) remain significant, the incidence of congestive heart failure continues to increase, and there is a need to provide better cardioprotection (therapy that reduces the amount of necrosis that may be coupled with better clinical outcome) in the setting of AMI. Since the introduction of the concept of cardiac protection over a quarter of a century ago, various interventions have been investigated to reduce myocardial infarct size. Intravenous beta-blockers administered in the early hours of infarction were clearly shown to be of benefit. Intravenous adenosine appeared promising for anterior wall AMIs, as did cariporide in some studies. Glucose-insulin-potassium infusion was beneficial in certain subgroups of patients, particularly diabetics. A variety of other medications were studied with negative or marginal results. The best strategy to limit infarct size is early reperfusion with percutaneous coronary stenting or thrombolytic therapy. Stenting is superior and should be adopted whenever there is a qualified laboratory available. Available resources should focus on decreasing time from onset of symptoms to start of reperfusion and maintaining vessel patency. Future studies powered to better assess clinical outcome are needed for adjunctive therapy with adenosine, K(ATP) channel openers, Na(+)/H(+) exchange inhibitors, and hypothermia.