The core components of the Hippo pathway are conserved from flies to mammals. In humans, these include a kinase cascade initiated by the Hippo kinase MST1/2 associated with the adaptor protein WW45/SAV1, and LATS1/2 in complex with MOB1, which in turn, phosphorylates and inhibits the mammalian transcription co-activator YAP and its related protein TAZ. YAP plays a critical role in organ size control during development, and its persistent nuclear localization and activation contributes to multiple human malignancies. The mechanisms driving YAP activation in most cancers, however, are often not clearly understood. In recent studies, we and Guan's team found that YAP activation represents a key molecular event contributing to uveal melanoma, the most frequent ocular malignancy in adults. Uveal melanoma growth is driven by gain-of-function mutations in GNAQ or GNA11 oncogenes, encoding persistently active G protein α subunits of the Gq family. As the signaling capacity of G proteins and their coupled receptors (GPCRs) has been extensively investigated, these findings provided an opportunity to identify cancer-associated mechanisms resulting in YAP activation, and to explore whether YAP represents a suitable oncotarget for cancer treatment.