The vascular system has an important function of supplying tissues with oxygen and nutrients and clearing waste products. Therefore, the microvasculature must be sufficiently permeable to allow the free, bidirectional passage of small molecules and gases and, to a lesser extent, of plasma proteins. It is well recognized that vascular endothelial growth factor (VEGF) can increase vascular permeability, thus playing important roles in variety of disorders, including diabetic retinopathy, nephrotic syndrome, brain edema, acute respiratory distress syndrome, and sepsis-associated hypotension. However, how vascular permeability is controlled by anti-permeable factors is not fully understood. We have recently found that pigment epithelium-derived factor (PEDF), a 50kD glycoprotein, inhibits retinal, renal and brain hyperpermeability by counteracting the biological actions of VEGF. In this review, we discuss about the pathophysiological role of PEDF in vascular permeability, especially focusing on retinal- renal disorders.