Parapneumonic pleural effusions (PPE) and pleural empyema (PE) present a frequently diagnostic and therapeutic challenge in clinical practice. Although pleural diseases have received increased attention during the past decade, there are still many unanswered questions concerning the diagnosis and treatment of PPE and PE. A lack of controlled studies concerning the management of PPE and PE was noted in recent guidelines. The use of fibrinolytics intrapleurally appears to enhance intercostals tube drainage, reducing the requirement for subsequent surgical mechanical debridement. Recently, there has been interest in other intrapleural agents including combination drugs consisting of streptokinase and streptodornase-α, Dnase. Factors to be considered in evaluating whether or not intrapleural instillation of fibrinolytics is effective include an assessment of clinical responses. This review discusses the use of fibrinolytic agents as a novel therapeutic options for treating the various stages of parapneumonic effusions and empyemas.