Two genes are considered synthetic lethal if mutation of either alone allows cell viability, whereas simultaneous mutation leads to cell death. A synthetic lethal screen unveiled the dependency of Wnt/beta-catenin-addicted colorectal cancer cells on vascular endothelial growth factor receptor-1 kinase activity and suggested a novel therapeutic approach for this malignancy. (Clin Cancer Res 2009;15(24):7453-5)