The protein β-catenin is an essential component of intercellular junctions and the Wnt growth factor signaling pathway. In many cancers, mutation of Wnt pathway components leads to activation of oncogenes by the β-catenin–Tcf transcription factor complex. This complex is therefore an attractive target for anti-cancer drugs, but any such compound must selectively interfere with the β-catenin–Tcf complex without disrupting other essential interactions of β-catenin. Recent structural and biochemical studies have probed the molecular basis of ligand interaction by β-catenin, and highlighted the possibilities and challenges of designing inhibitors of the β-catenin–Tcf complex.