The hallmark of acute ST-segment elevation myocardial infarction is complete thrombotic occlusion of the infarct-related artery. Reperfusion strategies over the past 25 years have focused on the early restoration of flow in the epicardial artery. More recently, through enhanced understanding of the microvasculature, the open artery hypothesis has moved downstream to also include the complete and early restoration of microvascular flow. Fibrinolytic monotherapy has a ceiling of efficacy, but is universally available. Improvement of early artery patency can be achieved with the addition of a platelet glycoprotein IIb/IIIa receptor antagonist. Mechanical revascularization, via percutaneous coronary intervention, is superior to pharmacologic therapy, but can have limited accessibility. Perhaps the optimal strategy will involve a combination of pharmacologic and mechanical modalities.