Chemical genomics is a powerful method to complement more traditional genetic techniques (i.e. knockout mice, siRNA) for the dissection of complex signaling networks. Wnt signaling in mammals is a complex and crucial regulator of diverse functions. The Wnt-β-catenin pathway initiates a signaling cascade that is crucial in both normal development and the initiation and progression of cancer. A key step in Wnt activation of target genes is the nuclear translocation of β-catenin and the formation of a complex between β-catenin and members of the T-cell factor (TCF) family of transcription factors. Using a forward chemical genomics strategy, we identified ICG-001, a selective inhibitor of a subset of Wnt-β-catenin-driven gene expression. This chemogenomic tool enables us to dissect this complex signaling network and to better understand the role of Wnt signaling in both normal and pathophysiological settings.