There is widespread interest in the use of the angiogenic cytokine, vascular endothelial growth factor (VEGF), for the treatment of cardiovascular disease. The main paradigm for VEGF cardiovascular therapy is the stimulation of "therapeutic angiogenesis" in ischemic myocardial and peripheral vascular limb disease. In this review, approaches to VEGF therapy based on the therapeutic angiogenesis model are critically assessed, and the alternative mechanism of vascular protection is advanced. Vascular protection is defined as the 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. VEGF-induced synthesis of NO and prostacyclin are both likely to be key mediators of VEGF-dependent vascular protection. Investigation into vascular protection should help us to gain insight into the underlying mechanisms of the cardiovascular actions of VEGF and should prove valuable in the development of novel therapeutic approaches based on local VEGF gene delivery.