The immediate goal of reperfusion in acute ST-elevation myocardial infarction (STEMI) is the prompt restoration of myocardial blood flow. Over the past 50 years, numerous advances have been made in achieving this goal by combining pharmacologic regimens with primary percutaneous coronary intervention (PCI) [i.e. pharmacoinvasive recanalizaton]. Fibrinolytics and glycoprotein (GP) IIb/IIIa inhibitors remain the most promising and widely used pharmacologic agents used to date. Early GP IIb/IIIa inhibition in patients undergoing PCI for STEMI results in early reperfusion and can result in improved clinical outcomes. Combination therapy with fibrinolytics and GP IIb/IIIa inhibitors is currently under investigation. The importance of time in the administration of these agents, especially in patients with expected delays to mechanical reperfusion, cannot be overemphasized. Benefits of revascularization are dependent on establishing reperfusion early enough to salvage the myocardium and preserve the left ventricular ejection fraction. As time passes, the effectiveness of treatments decline and patient outcomes are worse. This dependence upon time applies to both fibrinolytic therapy as well as primary PCI. In the current era, primary PCI is the preferred modality for treating patients with STEMI with a goal door-to-balloon time of <90 minutes. However, this modality is not available to all patients presenting with STEMI. Given the importance of time to reperfusion, a pharmacoinvasive approach may be ideal for this patient population. In this paper, we review the literature on pharmacoinvasive recanalization and discuss the optimal combination and timing of these agents. We have linked current American College of Cardiology/American Heart Association Clinical Practice Guidelines to clinical data available in the literature.