The Hippo pathway, a conserved signaling cascade in both *Drosophila* and mammals, plays a crucial role in regulating cell number by modulating cell proliferation, cell death, and cell differentiation. Recent studies have identified numerous upstream regulators of the Hippo pathway, including cell polarity, mechanotransduction, and G-protein-coupled receptor (GPCR) signaling. The actin cytoskeleton and cellular tension appear to integrate and transmit these upstream signals to the core Hippo signaling cascade. This review discusses the regulatory mechanisms of the Hippo pathway and its implications in various physiological and pathological conditions. The Hippo pathway is involved in tissue homeostasis, organ size control, stem cell maintenance, and tissue regeneration. In pathological conditions, dysregulation of the Hippo pathway can lead to tumor formation and organ degeneration. The review also highlights the connection between the Hippo pathway and cancer development, particularly the role of YAP/TAZ in promoting cancer metastasis and sustaining cancer stem cell self-renewal. Understanding the regulation of the Hippo pathway is essential for developing therapeutic interventions targeting this pathway in diseases such as cancer.The Hippo pathway, a conserved signaling cascade in both *Drosophila* and mammals, plays a crucial role in regulating cell number by modulating cell proliferation, cell death, and cell differentiation. Recent studies have identified numerous upstream regulators of the Hippo pathway, including cell polarity, mechanotransduction, and G-protein-coupled receptor (GPCR) signaling. The actin cytoskeleton and cellular tension appear to integrate and transmit these upstream signals to the core Hippo signaling cascade. This review discusses the regulatory mechanisms of the Hippo pathway and its implications in various physiological and pathological conditions. The Hippo pathway is involved in tissue homeostasis, organ size control, stem cell maintenance, and tissue regeneration. In pathological conditions, dysregulation of the Hippo pathway can lead to tumor formation and organ degeneration. The review also highlights the connection between the Hippo pathway and cancer development, particularly the role of YAP/TAZ in promoting cancer metastasis and sustaining cancer stem cell self-renewal. Understanding the regulation of the Hippo pathway is essential for developing therapeutic interventions targeting this pathway in diseases such as cancer.