The α4 laminin subunit is a component of the basement membrane of blood vessels where it codistributes with the integrins αvβ3, α3β1, and α6β1. An antibody against the G domain (residues 919-1207; G^919–1207) of the α4 laminin subunit inhibits angiogenesis in a mouse–human chimeric model, indicating the functional importance of this domain. Additional support for the latter derives from the ability of recombinant G^919–1207 to support endothelial cell adhesion. In particular, endothelial cell adhesion to G^919–1207 is half-maximal at 1.4 nM, whereas residues 919-1018 and 1016–1207 of the G domain are poor cellular ligands. Function blocking antibodies against integrins αvβ3 and β1 and a combination of antibodies against α3 and α6 integrin subunits inhibit endothelial cell attachment to G^919–1207. Moreover, both αvβ3 and α3β1 integrin bind with high affinity to G^919–1207. Together, our studies demonstrate that the G domain of laminin α4 chain is a specific, high affinity ligand for the αvβ3 and α3β1 integrin heterodimers and that these integrins, together with α6β1, function cooperatively to mediate endothelial cell–α4 laminin interaction and hence blood vessel development. We propose a model based on these data that reconcile apparent discrepancies in the recent literature with regard to the role of the αvβ3 integrin in angiogenesis.