Interactions between β-catenin and LEF-1/TCF, APC and conductin/axin are essential for wnt-controlled stabilization of β-catenin and transcriptional activation. The wnt signal transduction pathway is important in both embryonic development and tumor progression. We identify here amino acid residues in β-catenin that distinctly affect its binding to LEF-1/TCF, APC and conductin. These residues form separate surface clusters, termed hot spots, along the armadillo superhelix of β-catenin. We also show that complementary charged and hydrophobic amino acids are required for formation of the bipartite β-catenin–LEF-1 transcription factor. Moreover, we demonstrate that conductin/axin binding to β-catenin is essential for β-catenin degradation, and that APC acts as a cofactor of conductin/axin in this process. Binding of APC to conductin/axin activates the latter and occurs between their SAMP and RGS domains, respectively.