Evidence from Drosophila and cultured cell studies supports a role for heterotrimeric guanosine triphosphate–binding proteins (G proteins) in Wnt signaling. Wnt inhibits the degradation of the transcriptional regulator β-catenin. We screened the α and βγ subunits of major families of G proteins in a Xenopus egg extract system that reconstitutes β-catenin degradation. We found that Gα_o, Gα_q, Gα_i2, and Gβγ inhibited β-catenin degradation. Gβ₁γ₂ promoted the phosphorylation and activation of the Wnt co-receptor low-density lipoprotein receptor–related protein 6 (LRP6) by recruiting glycogen synthase kinase 3 (GSK3) to the membrane and enhancing its kinase activity. In both a reporter gene assay and an in vivo assay, c-βARK (C-terminal domain of β-adrenergic receptor kinase), an inhibitor of Gβγ, blocked LRP6 activity. Several components of the Wnt–β-catenin pathway formed a complex: Gβ₁γ₂, LRP6, GSK3, axin, and dishevelled. We propose that free Gβγ and Gα subunits, released from activated G proteins, act cooperatively to inhibit β-catenin degradation and activate β-catenin–mediated transcription.