Despite their many abnormalities, cancer cells often retain a powerful dependency on lineage master regulators for their growth and viability. The strength of this dependency in cancer often exceeds the requirements for normal tissue homeostasis, which has led to a widespread interest in developing small-molecule modulators of transcription factor function for therapeutic purposes. However, our knowledge of transcription factor biochemistry is still in a primitive state. In our lab, we have taken a genetic screening strategy that seeks to reveal novel molecular mechanisms employed by transcription factors to support cancer cell viability. In my presentation, I will present a discovery we have made regarding Hippo signaling, which is a developmental pathway that is pervasively dysregulated in human cancer. The net result of Hippo dysfunction is an aberrant requirement for TEAD:YAP/TAZ transcriptional complexes to support carcinoma and sarcoma maintenance. Using a paralog co-targeting genetic screening campaign, we have identified a pair of redundant kinases that are dedicated to supporting YAP/TAZ function in cancer, an aspect of Hippo signaling that has been previously overlooked. These findings suggest a novel catalytic vulnerability in Hippo-dysregulated cancers, which might allow for novel pharmacology that can eliminate YAP/TAZ-addicted tumors.