Early achievement of TIMI 3 (normal) flow in the infarct-related artery is the goal of therapy of acute myocardial infarction (AMI) in order to reduce infarct size and improve clinical outcome. By the mid 1990s mechanical treatment (primary angioplasty) has been recognized as the best method to gain this goal but fibrinolysis still remains the standard of care because of logistic limitations of angioplasty. Benefit of aspirin in association with fibrinolytic drugs encouraged the use of antagonists of the glycoprotein IIb/IIIa receptor (abciximab, eptifibatide, tirofiban), which block the final common pathway of platelet aggregation in AMI therapy. In dose-finding and dose-confirmation studies the combination of a fibrinolytic agent with a glycoprotein IIb/IIIa receptor antagonist, such as abciximab, resulted in nearly 80% of patients achieving complete reperfusion at 90 min without a substantial increase in side effects. This combination was tested in the phase III GUSTO V study. Compared to full-dose reteplase alone, the association of half-dose of reteplase and abciximab significantly reduced most non-fatal complications of myocardial infarction such as reinfarction and need of urgent revascularization. Failure to show a reduction in mortality with "combo therapy" must be related to the low 30-day mortality observed in both arms of the study, the lowest ever found in fibrinolytic trials. Warning about an increase in non-intracranial bleeding is counterbalanced by similar rates of intracranial hemorrhages and non-fatal disabling strokes in the two groups. On the basis of the GUSTO V results it appears clear that future advances in the management of AMI will only be possible by combining different reperfusion modalities (lytics, IIb/IIIa antagonists and coronary angioplasty). Whichever is the best combination, mechanical reperfusion will play a central role in the management of AMI. A major challenge for cardiologists will be reinforcement of collaboration and synergy between institutions with different levels of resources.