Many colorectal cancers are caused by disrupted Wnt signalling. During normal Wnt signalling, activation of the pathway inhibits the Adenomatous Polyposis Coli (APC) complex, allowing β-catenin to accumulate and associate with Legless (Lgs) and TCF DNA-binding proteins, leading to the expression of target genes. In 80% of cases of colorectal cancer, APC is inactivated, causing an increase in β-catenin levels and constitutive gene activation. Hoffmans and Basler(p. 4393) reasoned that specific interference of the β-catenin/Lgs association would prevent constitutive gene activation and halt the progression of cancer, and they use Drosophila to investigate this potential drug target. They show that the association between Lgs and β-catenin (Armadillo in Drosophila) is dependent on two of the acidic amino acid residues in Armadillo. This putative contact site is highly specific to Lgs, and its disruption severely reduces Wnt-activated gene expression. The researchers conclude that the β-catenin/Lgs interaction could be a target for therapeutic intervention.