Virtually, every pulmonary disease and most non-pulmonary diseases may be associated with a pleural effusion. The presence of a pleural effusion allows the clinician to ‘diagnose’ or narrow the differential diagnosis and aetiology of the fluid collection. However, pleural fluid analysis (PFA) in isolation rarely provides a definitive diagnosis. This review discusses the rationale for evaluating patients with a pleural effusion. If the clinician obtains a detailed history, performs a comprehensive physical examination, reviews pertinent blood tests, and evaluates the chest imaging findings prior to thoracentesis, there should be a high likelihood of establishing a firm clinical diagnosis based on the appropriate PFA. This manuscript reviews the clinical presentation, chest imaging findings, duration and natural course of specific pleural effusions to help narrow the range of pre-thoracentesis diagnoses. A diagnosis of transudative effusion confirms an imbalance in hydrostatic and oncotic pressures, normal pleura and a limited differential diagnosis, which is typically apparent from the clinical presentation. Exudates are the result of infections, malignancies, inflammation, impaired lymphatic drainage or the effects of drugs, and pose a greater diagnostic challenge. The differential diagnosis for a pleural exudate can be narrowed if LDH levels exceed 1000 IU/L, the proportion of lymphocytes is ≥80%, pleural fluid pH is <7.30 or there is pleural eosinophilia of >10%.