Integrins mediate cell adhesion to the extracellular matrix and transmit signals within the cell that stimulate cell spreading, retraction, migration, and proliferation. The mechanism of integrin outside-in signaling has been unclear. We found that the heterotrimeric guanine nucleotide-binding protein (G protein) G alpha(13) directly bound to the integrin beta(3) cytoplasmic domain and that G alpha(13)-integrin interaction was promoted by ligand binding to the integrin alpha(IIb)beta(3) and by guanosine triphosphate (GTP) loading of G alpha(13). Interference of G alpha(13) expression or a myristoylated fragment of G alpha(13) that inhibited interaction of alpha(IIb)beta(3) with G alpha(13) diminished activation of protein kinase c-Src and stimulated the small guanosine triphosphatase RhoA, consequently inhibiting cell spreading and accelerating cell retraction. We conclude that integrins are noncanonical G alpha(13)-coupled receptors that provide a mechanism for dynamic regulation of RhoA.