Many human diseases are characterized by disorders of the vasculature. In ischemic heart disease or peripheral artery disease, insufficient blood vasculature leads to tissue ischemia. Out of the many players in the angiogenesis field, the vascular endothelial growth factors are by far the best characterized and several VEGFs have already entered clinical use in a variety of human conditions. While many studies have addressed the role of angiogenesis and the blood vasculature in human physiology and pathology, the role of proangiogenic therapy in PAD has until recently attracted very little attention. VEGF is the prime hypoxia inducible angiogenic factor and binds VEGFR-1 and VEGFR-2. VEGF increases permeability of the endothelium through the formation of intercellular gaps, vesico-vascular organelles, vacuoles as well as fenestrations. VEGF also causes vasodilatation through the induction of the endothelial nitric oxide synthase (eNOS) and the subsequent increase in nitric oxide production. In recent years, several studies have reported beneficial effects of VEGF when used as a proangiogenic therapy in the setting of tissue ischemia. While proangiogenic therapies could be employed in the treatment of various ischemic diseases,controlling these processes with targeted molecular therapies remains at the heart of research.