Both thrombolysis and primary percutaneous coronary intervention (PCI) are validated therapies in the treatment of ST-elevation acute myocardial infarction (STEMI). Primary PCI appears now to be more effective, provided the vessel patency is restored within 120 minutes. An approach combining the possibility of quickly starting a clot-dissolving medication with a subsequent PCI of the culprit lesion has therefore recently gained considerable interest. Facilitated percutaneous coronary intervention (PCI) refers to a pretreatment with any pharmacological agent allowing the achievement of some recanalization and possibly myocardial reperfusion, which might translate into an improved clinical outcome. Many drugs reduce the thrombus burden; however, the term "facilitated" is currently operatively restricted to glycoprotein GP-IIb-IIIa inhibitors, thrombolytic drugs, and their combination. Several earlier clinical trials tested the hypothesis that facilitated PCI in the setting of STEMI allows the achievement of a better myocardial reperfusion compared with primary PCI and that this benefit translates into an improved clinical outcome. However, after the first promising results, the recent ASSENT-4 trial has been prematurely interrupted because of higher in-hospital mortality in the group of patients who underwent full-dose tenecteplase followed by PCI compared with subjects undergoing primary PCI alone. After a critical review of the current knowledge, and pending the completion of ongoing trials, no clear evidence currently exists on the benefit of any systemic pharmacological facilitation of PCI beyond the upfront administration of dual oral antiplatelet therapy with aspirin and clopidogrel. While awaiting the results of a few other currently ongoing trials, facilitated PCI should now probably be restricted to the administration of glycoprotein IIb-IIIa inhibitors for patients at high risk of cardiovascular events and at low risk of bleeding when a more than 60-minute delay to primary PCI is anticipated. In patients having first medical contact within 3 hours, with an anticipated absolute delay to PCI of more than 90 minutes, thrombolysis can be safely recommended.