Vascular endothelial growth factor (VEGF) is essential for angiogenesis in health and pathophysiology, and it is currently a major focus for drug targeting in the development of treatments for diverse human diseases. Recently, we proposed that VEGF could also play a role as a vascular protective factor in the adult vasculature and in disease. In this model, vascular protection is defined as a VEGF-induced enhancement of endothelial functions that mediate the inhibition of vascular smooth muscle cell proliferation, enhanced endothelial cell survival, suppression of thrombosis, and anti-inflammatory effects. A feature of this model is that protective effects of VEGF are essentially independent of angiogenesis or endothelial cell proliferation. VEGF-dependent cell survival and VEGF-induced synthesis of nitric oxide and prostacyclin are likely to be key mediators of a vascular protective effect. Vascular protection should help to improve insight into the underlying mechanisms of cardiovascular actions of VEGF and prove valuable for developing novel therapeutic approaches to cardiovascular disease.