Background: Aberrant β-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate β-catenin activity for therapeutic purposes have proven elusive to date. Methodology: To uncover genetic dependencies in breast cancer cells that harbor active β-catenin signaling, we performed RNAi-based loss-of-function screens in breast cancer cell lines in which we had characterized β-catenin activity. Here we identify CSNK1E, the gene encoding casein kinase 1 epsilon (CK1ε) as required specifically for the proliferation of breast cancer cells with activated β-catenin and confirm its role as a positive regulator of β-catenin-driven transcription. Furthermore, we demonstrate that breast cancer cells that harbor activated β-catenin activity exhibit enhanced sensitivity to pharmacological blockade of Wnt/β-catenin signaling. We also find that expression of CK1ε is able to promote oncogenic transformation of human cells in a β-catenin-dependent manner. Conclusions/Significance: These studies identify CK1ε as a critical contributor to activated β-catenin signaling in cancer and suggest it may provide a potential therapeutic target for cancers that harbor active β-catenin. More generally, these observations delineate an approach that can be used to identify druggable synthetic lethal interactions with signaling pathways that are frequently activated in cancer but are difficult to target with the currently available small molecule inhibitors.