The primary goal of therapy for acute ST-segment elevation myocardial infarction (STEMI) is rapid, complete, and sustained restoration of infarct-related artery (IRA) blood flow. Both pharmacologic and mechanical restoration of antegrade coronary blood flow in patients with STEMI have been demonstrated to improve left ventricular function, to reduce infarct size, and to reduce mortality. The benefits of myocardial reperfusion, including prevention of infarct expansion, reduction of ventricular remodeling, and improvement of electrical stability, are amplified when IRA patency can be achieved quickly after the onset of symptoms, particularly in the first 2 hours—a time window that is particularly challenging for mechanical methods of reperfusion, even at high-volume percutaneous coronary intervention centers. Despite this demonstrated clinical benefit of reperfusion therapy, substantial challenges exist in identifying the precise combination of therapeutic agents and strategies that will maximize patient outcomes. This review focuses on the evolving pharmacologic treatment strategies for STEMI.