Vascular endothelial growth factor (VEGF)-A plays a critical role in vascular development and angiogenesis through its binding and activation of VEGF receptor-2 (VEGFR-2). The binding of VEGF-A to VEGFR-2 causes receptor dimerization, kinase activation and autophosphorylation of specific tyrosine residues within the dimeric complex. Tyrosine(Y)951 in the kinase-insert domain, Y1054 and Y1059 in the kinase domain and Y1175 and Y1214 in the C-terminal tail have been shown to serve as autophosphorylation sites. Phosphorylated Y1175 creates a binding site for phospholipase Cgamma1 (PLC-gamma1) and Shb. Activation of PLC-gamma1 and Shb regulates VEGF-A-dependent cell proliferation and cell migration, respectively. Phosphorylated Y951 binds and mediates tyrosine phosphorylation of the T-cell-specific adaptor protein (TSAd), which is expressed in endothelial cells. Y951-mediated coupling of VEGFR-2 and TSAd is critical for VEGF-A-induced cell migration and actin reorganization, and for pathological angiogenesis. These phosphorylation sites may be useful targets for the development of anti-angiogenic therapies to treat atherosclerosis and cancer.