The advances of our understanding in the Hippo signaling as a key regulatory pathway of proliferation and apoptosis have provided mechanical insights for controlling organ size and tumorigenicity. Recently, much attention was given to the regulation of LATS1/2 (large tumor suppressor) kinases that phosphorylate YAP/TAZ, a transcriptional co-activator in the Hippo pathway, and control the level and nuclear localization of YAP/TAZ. In our recent work, we showed that deubiquitinase YOD1 stabilizes ITCH and facilitates ITCH-mediated LATS1/2 ubiquitination and degradation, which results in increased YAP/TAZ level. Furthermore, we found that the YOD1-ITCH-LATS1/2-YAP/TAZ signaling axis is controlled by the differential expression of miR-21 in a cell-density-dependent manner. Using a transgenic mouse model, we showed that the inducible expression of YOD1 enhances the proliferation of hepatocytes and leads to hepatomegaly in a YAP/TAZ-activity-dependent manner. Moreover, we found a strong correlation between YOD1 and YAP expression in liver cancer patients. Overall, our data suggest that YOD1 is a novel regulator of Hippo pathway and thereby a potential therapeutic target for liver cancer.