Numerous randomized trials have unequivocally shown that fibrinolytic therapy in the treatment of ST-segment elevation myocardial infarction substantially reduces mortality when administered within 12 hours of symptom-onset. Although fibrinolytic therapy initially restores antegrade flow in the infarct vessel in the majority of patients, sustained tissue-level reperfusion occurs in only approximately 25% of patients. Thrombin and platelets are two additional constituents of a coronary thrombus that contribute to the tendency for vessel reocclusion after initially successful reperfusion. Therefore, adjunctive therapy with potent antithrombins and antiplatelets is essential in the successful treatment of a coronary thrombus. Recent studies including GUSTO-V and ASSENT-III have studied the use of combination drug therapy with glycoprotein IIb/IIIa inhibition and reduced-dose fibrinolytics in the treatment of acute myocardial infarction. These studies demonstrated that combination therapy reduces reinfarction rates. However, this therapy is associated with increased bleeding complications especially in elderly patients. This article reviews the results and clinical implications of these major trials of combination drug therapy in acute myocardial infarction and provides recommendations for tailoring their use in clinical practice.