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Fibrinolytic therapy for hemothorax and empyema was introduced into clinical practice over 50 years ago and remains part of the therapeutic armamentarium today. The use of fibrinolysins in this situation is predicated on the concept that intrapleural organization and fibrosis can be prevented by augmentation of intrapleural fibrinolytic activity. A number of plasminogen activators have been used to effect intrapleural fibrinolysis, including streptokinase, urokinase, and tissue plasminogen activator. All these agents increase intrapleural fibrinolytic activity by increasing local generation of plasmin. Intrapleural fibrinolytic therapy does not induce systemic fibrinolysis and is generally well tolerated. Fibrinolytic therapy remains a treatment option for selected patients with intrapleural loculation associated with parapneumonic effusions or organizing hemothorax, but its efficacy in these contexts remains controversial and is being evaluated in ongoing clinical trials.