Src kinase activity was found to protect endothelial cells from apoptosis during vascular endothelial growth factor (VEGF)–, but not basic fibroblast growth factor (bFGF)–, mediated angiogenesis in chick embryos and mice. In fact, retroviral targeting of kinase-deleted Src to tumor-associated blood vessels suppressed angiogenesis and the growth of a VEGF-producing tumor. Although mice lacking individual Src family kinases (SFKs) showed normal angiogenesis, mice deficient in pp60^c-src or pp62^c-yes showed no VEGF-induced vascular permeability (VP), yet fyn^−/− mice displayed normal VP. In contrast, inflammation-mediated VP appeared normal in Src-deficient mice. Therefore, VEGF-, but not bFGF-, mediated angiogenesis requires SFK activity in general, whereas the VP activity of VEGF specifically depends on the SFKs, Src, or Yes.