Empyema thoracis, also known as pleural infection, represents a significant challenge due to its association with substantial morbidity, prolonged hospitalization, and healthcare resource utilization. The medical treatment of empyema aims to achieve sepsis control, promote pleural drainage, and preserve lung function. This chapter reviews the current principles and evolving strategies in the nonsurgical treatment of empyema, encompassing antibiotic therapy, chest tube drainage, and adjunctive intrapleural interventions. Empirical antibiotic therapy should be started promptly and guided by local microbiological patterns, with subsequent tailoring based on culture and sensitivity results. Image-guided chest tube placement should be performed at the earliest opportunity following diagnosis. In cases of ongoing systemic inflammatory response with significant residual collection and persistently raised inflammatory markers beyond 48 hours of treatment, early thoracic CT scanning and surgical referral constitute a key step in medical management. In the absence of prompt access to thoracic surgery, a combination of intrapleural fibrinolytic and enzyme therapy, specifically with tissue plasminogen activator (tPA) and deoxyribonuclease (DNase), carries the best evidence base. In the absence of alteplase, the use of urokinase as a lesser alternative fibrinolytic may be appropriate. The use of fibrinolytic monotherapy is not recommended. In the presence of restricted access, poor surgical candidacy, or contraindications to intrapleural fibrinolytic therapy due to high bleeding risk, intrapleural saline irrigation offers an important rescue treatment option. In the context of a non-expandable “trapped” lung and a chronically infected pleural space with no suitable surgical options, prolonged antibiotic therapy aided by an indwelling pleural catheter may be considered.