The YAP oncoprotein, a transcriptional coactivator that can bind to multiple DNA-binding transcription factors such as Smad, Runx, and TEAD/TEF, has been linked to a wide spectrum of human cancers. The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth. In this study by Pan and colleagues, the authors investigate whether TEAD may be exploited for selective inhibition of oncogenic growth driven by YAP hyperactivation. The authors demonstrate that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or NF2/Merlin inactivation. In addition, verteporfin is identified as a small molecule that inhibits TEAD–YAP association and YAP-induced liver overgrowth. Thus, this study provides insights into novel mechanisms regulating YAP-induced tumorigenesis.