The combined use of a fibrinolytic and a platelet glycoprotein (GP) IIb/IIIa receptor inhibitor to target the fibrin and platelet components of occlusive thrombi offers the potential for more rapid and complete reperfusion in patients with acute myocardial infarction (MI), although there have been concerns about the safety of this combination therapy. Data from the recent GUSTO-V and the ASSENT-3 trials support the use of this regimen in that the 30-day death or nonfatal reinfarction rate (7 days) in GUSTO-V and death or in-hospital reinfarction or in-hospital refractory ischemia rate in ASSENT-3 were reduced (p = 0.001 and p = 0.0001, respectively). The need for revascularization in both these trials was also reduced significantly. There was no increased risk of intracranial hemorrhage or stroke with the combination therapy, but an increased rate of nonintracranial severe or major bleeding was observed. At present, patients aged > 75 years should not receive combination therapy. Further studies in subgroup patient populations are warranted.