Thrombolytic agents have become the corner stone in the treatment of acute myocardial infarction. However, the current agents are far from perfect. New thrombolytic drugs have been designed to overcome these shortcomings. Development of these agents has focused not only on increasing plasma half-life and thus allowing single-bolus administration, but also on improving fibrin specificity and resistance to plasminogen activator inhibitor. The safety and efficacy of several of these promising thrombolytic drugs have been evaluated in large-scale trials, which are discussed in the present review. Parallel to these advances, alternatives to standard thrombolytic regimens have been developed. New trials evaluating the combination of reduced-dose fibrinolytics with different regimens of antithrombotic agents will optimize future reperfusion strategies.