This review takes a critical look at the current effectiveness of reperfusion therapy for acute myocardial infarction and at the potential for cardioprotective agents to improve it. Reperfusion alone limits the median value of infarct size to approximately 50% of the ischemic region. However, the range of infarct sizes is very wide, and one-fourth of these patients have more than 75% of the ischemic zone infarcted despite successful coronary reperfusion. Available studies suggest that mortality and morbidity is increased when more than 20% of the left ventricle is infarcted. Therefore, to be effective infarct size-limiting therapy would have to reduce infarction to or below this 20% target. To achieve this goal in the quartile of patients with the biggest infarcts the cardioprotective agent would have to be potent enough to reduce infarct size from its current value of 75% of the ischemic zone to 40% or less. While ischemic preconditioning and some pretreatment drugs might be potent enough to achieve this goal, few of the agents given at the clinically relevant time of at or just before reperfusion have exhibited such potency. Several cardioprotective agents have recently been evaluated in clinical trials but their results have been disappointing. Some of the poor clinical trial performance may stem from study designs which fail to identify those patients falling within the upper quartile of infarct sizes, presumably the only group that would be expected to actually benefit from a reduction in infarct size. Other possible causes could be that co-morbidities or drugs patients are taking may block the pathways involved in the anti-infarct effect or that the drugs simply do not protect even in animal models. Few agents have been thoroughly tested in clinically relevant animal models prior to their testing in man.