The benefits of coronary thrombolysis appear to depend primarily on achieving and maintaining coronary artery patency. Unfortunately, failure of coronary thrombolysis or recurrent occlusion may occur in up to 40% of patients treated with fibrinolytic agents. Results of recent studies suggest that recurrent thrombosis may be due to multiple factors including: plasmin-mediated activation of the coagulation system, procoagulant activity of the residual thrombus, presence of high shear forces that promote platelet deposition, and attenuation of physiologic fibrinolytic activity after pharmacologic thrombolysis. Preliminary data suggest that recently developed novel anticoagulants and antiplatelet agents may improve the rate of initial recanalization and prevent recurrent thrombus.