It is clear that survival and better outcomes after acute myocardial infarction (AMI) are dependent on rapid, complete, and sustained reperfusion of the affected myocardium. Thrombolytic therapy is currently the most common reperfusion strategy in AMI, however, a significant proportion of patients fail to reach reperfusion with this form of therapy. There is evidence from randomized trials that rescue percutaneous coronary intervention (PCI) for failed thrombolysis may convey better outcomes to patients when compared to a conservative management. Nevertheless, it is not surprising that in this inherently thrombogenic milieu, rescue PCI has a lower success rate and a high incidence of rethrombosis, which have a profoundly negative impact on the outcome of patients. Platelets are thought to play a central role in the pathophysiology of failed thrombolysis and in the thrombotic complications following PCIs. Therefore, platelet glycoprotein (GP) IIb/IIIa antagonist may be of benefit in the setting of rescue PCI. Two retrospective subgroup analyses have suggested that these potent antiplatelet agents may improve the outcome of patients undergoing rescue PCI after failed full-dose thrombolytic therapy. An increase in major bleeding, however, has also been noted. Therefore, in light of the lack of evidence deriving from randomized, placebo-controlled trials, careful consideration of several aspects relevant to this setting is needed before GP IIb/IIIa antagonists are administered in rescue percutaneous coronary procedures.