Vascular endothelial growth factor (VEGF) is one of the main endogenous pro-angiogenic cytokines. Inhibition of the VEGF signaling pathways is an effective treatment for cancer patients. In addition, local anti- VEGF therapy was developed and established to treat proliferative diabetic retinopathy, age-related macular degeneration and retinal vein occlusion. For systemic administration of anti-VEGF drugs, serious side effects including hypertension or renal disorders have been observed. Evidence suggests that systemic effects might occur or develop in long-term treatment, despite limited resorption and minimal local side effects. Here, only limited data from clinical studies are available. The VEGF system is delicately balanced, and changes might result in deleterious effects. This review provides a brief overview of the VEGF-system, and summarizes its relevance in proliferative eye diseases. The anti-VEGF drugs locally used to treat different disease conditions are discussed with their local and systemic side effects.