Large efforts have been undertaken to develop more effective and safer thrombolytic agents than those currently used in clinical practice. In addition, the value of adjunctive agents influencing thrombotic and thrombolytic processes could be shown and newer agents are under active investigation. This review focuses on theoretical and practical aspects of optimizing thrombolytic therapy and mainly on genetically engineered, third generation plasminogen activators. Optimized thrombolytic therapy may make this form of therapy available to patients that are currently considered ineligible and it may lead to earlier, more complete reperfusion of infarct related coronary arteries. The benefits and risks of optimized thrombolytic regimens relative to mechanical reperfusion strategies will have to be constantly reassessed as both forms of treatment develop.