A new “Hippo” signaling pathway has been implicated in regulation of cell proliferation apoptosis, and tumorigenesis in Drosophila and mammalian. Hippo kinase, Salvador and Warts kinase (mammalian homologs: MST1/2, WW45, LATS1/2 respectively) are key molecules of this pathway. Hippo-Sav-Warts restricts cell proliferation and promoting apoptosis in differentiating epithelia by inhibiting Yorkie (mammalian homolog, YAP), a transcription co-activator. However, the roles and the molecular mechanisms of this pathway are not fully understood in mammals. Here, we have generated mice with either total or tissue-specific ablation of Hippo components (Mst1, Mst2 and WW45). Liver-specific WW45 cKO and Mst1/2 cKO mice showed expansion of hepatic progenitor cells (oval cells) and eventually develop hepatomas though inactivation of Yap1. Thus, the mammalian canonical Hippo pathway suppresses hepatocellular carcinoma development by inhibiting the proliferation of epithelial stem/progenitor cells. However, Mst1-null mice developed chemically- and genetically-induced lymphoma by inducing chromosomal instability, independently of YAP. Thus, we will discuss both canonical and noncanonical modes of action for Hippo components in tumor suppression.