The Hippo-YAP/TAZ signaling pathway plays a critical role in tissue homeostasis, tumorigenesis, and degeneration disorders. The regulation of YAP/TAZ levels is controlled by a complex regulatory network, where several feedback loops have been identified. However, it remains elusive how these feedback loops contain the YAP/TAZ levels and maintain the system in a healthy physiological state or trap the system in pathological conditions. Here, a mathematical model was developed to represent the YAP/TAZ regulatory network. Through theoretical analyses, three distinct states that designate the one physiological and two pathological outcomes were found. The transition from the physiological state to the two pathological states is mechanistically controlled by coupled bidirectional bistable switches, which are robust to parametric variation and stochastic fluctuations at the molecular level. This work provides a mechanistic understanding of the regulation and dysregulation of YAP/TAZ levels in tissue state transitions. Author summary: Tissue development and homeostasis require well-controlled cell proliferation. Lack of this control could lead to degenerative or tumorigenic diseases. Signaling pathways have been explored in promoting or inhibiting these diseases. The Hippo signaling pathway is one of these, which has been found to control tissue homeostasis and organ size through cell proliferation and apoptosis, as evidenced by extensive experimental data. However, the question remains of how tissue can transition from a homeostatic state to either a degenerative or tumorigenic state. By theoretically analyzing a mathematical model of its regulatory network, we present a mechanism that underlies Hippo signaling to control tissue transition from a homeostatic state to a disease state. This provides us a mechanistic understanding of how the parts of the regulatory network are coordinated for the transitions between the homeostasis state and the disease states. In addition, we looked at the role of system noise and found that it could promote the transition to one of the disease states. Our model allows for experimental hypotheses to be generated and could lead to the development of therapeutic strategies by targeting the Hippo signaling pathway. [ABSTRACT FROM AUTHOR]