Simple SummaryYAP/TAZ are the central effectors of the Hippo pathway and orchestrate their oncogenic program by binding to TEAD transcriptional factors. Here, we document a comprehensive understanding of how YAP/TAZ dependent tumors could be exploited for improving cancer therapies. Aside from providing the recent updates to the YAP/TAZ oncogenic pathway, we develop an exciting perspective on developing inhibitors that intervene with YAP/TAZ signaling with a close focus on the immune-microenvironmental regulations.AbstractVarious cancer cell-associated intrinsic and extrinsic inputs act on YAP/TAZ proteins to mediate the hyperactivation of the TEAD transcription factor-based transcriptome. This YAP/TAZ-TEAD activity can override the growth-limiting Hippo tumor-suppressor pathway that maintains normal tissue homeostasis. Herein, we provide an integrated summary of the contrasting roles of YAP/TAZ during normal tissue homeostasis versus tumor initiation and progression. In addition to upstream factors that regulate YAP/TAZ in the TME, critical insights on the emerging functions of YAP/TAZ in immune suppression and abnormal vasculature development during tumorigenesis are illustrated. Lastly, we discuss the current methods that intervene with the YAP/TAZ-TEAD oncogenic signaling pathway and the emerging applications of combination therapies, gut microbiota, and epigenetic plasticity that could potentiate the efficacy of chemo/immunotherapy as improved cancer therapeutic strategies.