β-catenin and Tcf4 are the downstream effectors of the Wnt signaling cascade. In colorectal cancer, mutations in Wnt cascade genes such as APC lead to the inappropriate formation of β-catenin/Tcf4 complexes. Earlier work has predicted that disruption of the β-catenin/Tcf4 protein-protein interaction could revert the proliferative phenotype of colorectal cancer cells. In this issue of Cancer Cell, Shivdasani and colleagues (Lepourcelet et al., 2004) have explored high-throughput screening of compound libraries in a search for small molecule inhibitors of the Wnt cascade. Ultimately, such inhibitors could become a novel class of smart anticancer drugs.