Upregulation of b-catenin, the primary mediator of the Wnt signaling pathway, plays an important role in the tumorigenesis of several types of human cancer. Targeting b-catenin to interfere with its ability to serve as a translational co-activator is considered an attractive therapeutic approach. However, the development of inhibitors has been challenging because of the lack of obvious binding pockets for ligands, and because inhibitors should not interfere with other b-catenin functions. Only two ligands with known molecular interactions with b-catenin have been developed so far, and are based on stabilized -helical peptides. In this study, we screened a large combinatorial library of bicyclic peptides by phage display. Binders to different surface regions of b-catenin were identified. The binding site of one group of ligands was mapped to the interaction region of the translational Wnt inhibitor ICAT (inhibitor of b-catenin and Tcf), which is a prime target site on b-catenin for therapeutic intervention, and to which no ligands could be developed before.