Combination thrombolytic therapy aims to achieve higher efficacy, higher specificity, better maintained patency of initially successfully reperfused vessels, less bleeding complications and cost containment by exploiting synergistic mechanisms of action and by using much lower doses of two drugs as in monotherapy. However, so far, no combination has been reported to yield significantly higher patency rates than rt-PA monotherapy. The combination of rt-PA and scuPA achieved high patency rates, and that with exquisite specificity. A combination of rt-PA and UK appears to prevent early reocclusion effectively, resulting in an overall improved clinical outcome versus monotherapy with either UK or rt-PA. The use of nonspecific plasminogen activators for the prevention of reocclusion may become obsolete, however, with the advent of more potent antithrombin and antiplatelet agents. Besides improved dosing regimens for monotherapy (front-loading), combination therapy has emerged as another possible means of enhancing thrombolytic efficacy by achieving effects that no single agent can produce. However, to date, no combination regimen has been documented to be clearly superior to monotherapy in a mortality trial.