Removal of mammalian Hippo kinase Mst1 and Mst2 in hepatocytes leads to very rapid hepatocellular carcinoma (HCC) formation, indicating that the Hippo signaling pathway is a critical gatekeeper in hepatocytes that restrains abnormal growth. By rigorous genetic approaches, we have identified an interacting network of the Hippo, Wnt/β-catenin and Notchsignaling pathways that controls organ size and HCC development. We found that in hepatocytes, loss of Mst1/2 led to activation of Notch signaling, which forms a positive feedback loop with Yap/Taz, transcription factors controlled by Mst1/2. This positive feedback loop resulted in severe liver enlargement and rapid HCC formation. Blocking the Yap/Taz-Notch positive feedback loop by Notch inhibition in vivo significantly reduced Yap/Taz activities, hepatocyte proliferation and tumor formation. Furthermore, we have uncovered a surprising inhibitory role of Wnt/β-catenin signaling to Yap/Taz activities that is important in tumor initiation. Genetic removal of β-catenin in the liver of the Mst1/2mutants significantly accelerates tumoriogenesis. Therefore, Wnt/β-catenin signaling that itself is known for oncogenic property exerts an unexpected function in restricting Yap/Taz and Notch activities in HCC initiation. The molecular interplay between the three signaling pathways identified in our study will provide new insights in developing new therapeutic strategies to treat liver tumors.