The Hippo signaling pathway is a central mechanism for regulating growth in multicellular organisms. It integrates mechanical, biochemical, and stress signals to control cell proliferation, survival, differentiation, and mechanics, thereby influencing organ development, homeostasis, and regeneration. Understanding the Hippo pathway's regulation and function is crucial for developing new therapies in regenerative medicine. This review provides an update on the molecular organization of the mammalian Hippo signaling network, discusses the regulatory signals and functional outputs of the pathway, and explores its roles in development and regeneration. The Hippo pathway was first identified in Drosophila through genetic screens for tumor suppressor genes. It consists of a kinase cascade involving MST1/2, LATS1/2, YAP/TAZ, and downstream effectors such as TEAD1–4. In mammals, the pathway is conserved, with YAP/TAZ as key downstream effectors. The pathway is regulated by various upstream signals, including biophysical, biochemical, metabolic, and stress cues. YAP/TAZ activity is modulated by the Hippo pathway, with high activity promoting cell proliferation and differentiation into helper cells, while low activity inhibits differentiation into worker cells. The Hippo pathway plays critical roles in organ development and regeneration. In the liver, YAP/TAZ activation promotes cholangiocyte differentiation and inhibits hepatocyte specification. In the intestine, YAP/TAZ is highly expressed in intestinal stem cells, promoting their proliferation and differentiation. In the heart, YAP/TAZ regulates cardiomyocyte proliferation and survival, with high activity promoting heart growth. In the brain, YAP/TAZ is expressed in neural progenitor cells and astrocytes, promoting their proliferation and differentiation. In the lungs, YAP/TAZ regulates airway morphogenesis and alveolarization. In the pancreas, YAP/TAZ promotes pancreatic progenitor self-renewal. The Hippo pathway is also involved in the development of skeletal muscle, skin, breasts, and eyes. The Hippo pathway is regulated by multiple upstream signals, including cell junctions, ECM properties, and stress signals. It is also involved in feedback regulation, with YAP/TAZ activity triggering compensatory activation of the Hippo pathway to prevent hyperactivation. The pathway's role in organ development is context-dependent, with YAP/TAZ activity varying between helper and worker cells. This classification is useful for understanding the functions of YAP/TAZ in organ development. Overall, the Hippo pathway is essential for regulating organ growth and development by balancing cell proliferation and differentiation.The Hippo signaling pathway is a central mechanism for regulating growth in multicellular organisms. It integrates mechanical, biochemical, and stress signals to control cell proliferation, survival, differentiation, and mechanics, thereby influencing organ development, homeostasis, and regeneration. Understanding the Hippo pathway's regulation and function is crucial for developing new therapies in regenerative medicine. This review provides an update on the molecular organization of the mammalian Hippo signaling network, discusses the regulatory signals and functional outputs of the pathway, and explores its roles in development and regeneration. The Hippo pathway was first identified in Drosophila through genetic screens for tumor suppressor genes. It consists of a kinase cascade involving MST1/2, LATS1/2, YAP/TAZ, and downstream effectors such as TEAD1–4. In mammals, the pathway is conserved, with YAP/TAZ as key downstream effectors. The pathway is regulated by various upstream signals, including biophysical, biochemical, metabolic, and stress cues. YAP/TAZ activity is modulated by the Hippo pathway, with high activity promoting cell proliferation and differentiation into helper cells, while low activity inhibits differentiation into worker cells. The Hippo pathway plays critical roles in organ development and regeneration. In the liver, YAP/TAZ activation promotes cholangiocyte differentiation and inhibits hepatocyte specification. In the intestine, YAP/TAZ is highly expressed in intestinal stem cells, promoting their proliferation and differentiation. In the heart, YAP/TAZ regulates cardiomyocyte proliferation and survival, with high activity promoting heart growth. In the brain, YAP/TAZ is expressed in neural progenitor cells and astrocytes, promoting their proliferation and differentiation. In the lungs, YAP/TAZ regulates airway morphogenesis and alveolarization. In the pancreas, YAP/TAZ promotes pancreatic progenitor self-renewal. The Hippo pathway is also involved in the development of skeletal muscle, skin, breasts, and eyes. The Hippo pathway is regulated by multiple upstream signals, including cell junctions, ECM properties, and stress signals. It is also involved in feedback regulation, with YAP/TAZ activity triggering compensatory activation of the Hippo pathway to prevent hyperactivation. The pathway's role in organ development is context-dependent, with YAP/TAZ activity varying between helper and worker cells. This classification is useful for understanding the functions of YAP/TAZ in organ development. Overall, the Hippo pathway is essential for regulating organ growth and development by balancing cell proliferation and differentiation.