Two high-affinity receptors for vascular endothelial growth factor (VEGF)-A, VEGFR1 and VEGFR2, cooperate for physiological vasculogenesis and angiogenesis in embryogenesis. VEGFR2 transduces the major signals for angiogenesis via its strong tyrosine kinase activity. However, unlike other representative tyrosine kinase receptors, VEGFR2 does not use the Ras pathway as a major downstream signaling but rather uses the phospholipase C-protein kinase C pathway to signal mitogen-activated protein (MAP)-kinase activation and DNA synthesis. Cell migration signals from VEGFR2 were recently shown to use, at least partly, a pathway dependent on the adaptor molecule TSAd from the kinase-insert region of VEGFR2. VEGFR2 is a direct and major signal transducer for pathological angiogenesis, including cancer and diabetic retinopathy, in cooperation with many other signaling partners; thus, VEGFR2 and its downstream signaling appear to be critical targets for the suppression of these diseases. More than 10 antagonists of VEGFR2, including kinase inhibitors and neutralizing antibodies, are now under clinical trials. Recently, the VEGFR2-specific ligand VEGF-E (also known as Orf-VEGF) family was extensively characterized. Interestingly, activation of VEGFR2 via VEGF-E in vivo results in a strong angiogenic response in mice, with minor effects on inflammation and hypervascular permeability compared with VEGF-A, suggesting that VEGF-E is a useful tool for proangiogenic therapy in ischemic diseases.