Difficult to diagnose pleural effusions are not uncommonly encountered in clinical practice. We define these effusions as those that remain undiagnosed after initial thoracentesis and repeat thoracentesis with pleural biopsy. Tuberculosis and malignancy are often found to be the underlying causes when a diagnosis is ultimately made, but other causes, including pulmonary embolism and intra-abdominal conditions, need to be considered as potential causes of the difficult to diagnose effusions. In selected cases, presumptive treatment of tuberculosis is indicated whereas in others, a decision must be made either to obtain a definitive diagnosis by invasive surgical procedures or to follow the patient with careful observation and watchful waiting.