Pleural effusion is common in clinical practice. Increased vascular permeability and leakage play a principal role in the development of exudative pleural effusions. In vitro and in vivo evidence have solidly established vascular endothelial growth factor (VEGF), a potent inducer of vascular permeability, as a crucial mediator in pleural fluid formation. VEGF is present in high quantities in human effusions. In the pleural space, mesothelial cells, infiltrating inflammatory cells, and (in malignant pleuritis) cancer cells contribute to the VEGF accumulation in the pleural fluids. Pleural fluid VEGF is biologically active and may promote tumor growth and chemotaxis. Strategies to antagonize the VEGF activity at various target points of its signaling pathway have shown success in vitro and in animal models of malignant pleural or peritoneal effusions. Novel agents targeting VEGF activities are undergoing clinical trials. Regulation of VEGF activity and vascular permeability represent a rapidly expanding field of research, which is likely to provide further insight in the pathophysiology of pleural fluid formation.