The Hippo tumor suppressor pathway was initially identified in the fruit fly to control tissue growth and organ size. Subsequent studies show that this pathway is highly conserved and also controls organ size in mammals. Hippo pathway controls organ size by regulating cell numbers. YAP and TAZ are two transcription factors that are inhibited by the Hippo pathway. Inhibition of YAP/TAZ represents the major functional output of the Hippo signaling. YAP and TAZ function to promote cell growth and organ size by promoting stem cell growth. Furthermore, mutation leading to dysregulation of the Hippo pathway is associated with cancer development. In fact, high YAP activity is frequently found in human cancer. Furthermore, TAZ has been shown to play important role in breast cancer stem cells. We have been investigating the mechanism of the Hippo pathway regulation and its role in stemness, differentiation, and tumorigenesis. We discovered the cell-cell contact and cell-matrix interaction play critical role in Hippo pathway regulation. In other words, the Hippo pathway can sense its neighbors and environment, and then relays these signals to tell the cell whether to proliferate, survive, or die. These functions are important for maintenance of both embryonic stem cells and tissue specific progenitor cells. Furthermore, we have identified hormones that act through G-protein coupled receptor to modulate the Hippo-YAP activity. These results suggest possible physiological cues that may regulate YAP activity to control tissue stem cells, therefore to influence organ size and tissue regeneration. Finally, we have isolated and characterized inhibitors that can modulate the Hippo pathway. These inhibitors are useful reagents for research and potential anti-cancer drugs. Importantly, our study shows that some of the FDA approved drugs can potently inhibits YAP. These novel findings gain new insights into the Hippo pathway regulation and provide valuable scientific knowledge of targeting the Hippo pathway for therapeutic intervention.