β-catenin is a central component of the cadherin cell adhesion complex and plays an essential role in the Wingless/Wnt signaling pathway. In the current model of this pathway, the amount of β-catenin (or its invertebrate homolog Armadillo) is tightly regulated and its steady-state level outside the cadherin–catenin complex is low in the absence of Wingless/Wnt signal. Here we show that the ubiquitin-dependent proteolysis system is involved in the regulation of β-catenin turnover. β-catenin, but not E-cadherin, p120 cas or α-catenin, becomes stabilized when proteasome-mediated proteolysis is inhibited and this leads to the accumulation of multi-ubiquitinated forms of β-catenin. Mutagenesis experiments demonstrate that substitution of the serine residues in the glycogen synthase kinase 3β (GSK3β) phosphorylation consensus motif of β-catenin inhibits ubiquitination and results in stabilization of the protein. This motif in β-catenin resembles a motif in IκB (inhibitor of NFκB) which is required for the phosphorylation-dependent degradation of IκB via the ubiquitin–proteasome pathway. We show that ubiquitination of β-catenin is greatly reduced in Wnt-expressing cells, providing the first evidence that the ubiquitin–proteasome degradation pathway may act downstream of GSK3β in the regulation of β-catenin.