Fibrosis is a pathological feature of most chronic inflammatory diseases, characterized by the excessive accumulation of extracellular matrix components, leading to organ dysfunction and death. It affects nearly every tissue in the body and is driven by key components of the innate and adaptive immune response, including the activation of ECM-producing myofibroblasts. Fibrosis is a major pathological feature of many chronic autoimmune diseases and influences tumor invasion, chronic graft rejection, and progressive myopathies. Despite increasing recognition of fibrosis as a major cause of morbidity and mortality in chronic inflammatory diseases, few treatments specifically target fibrosis pathogenesis. Fibrotic diseases are triggered by various factors, including genetic disorders, infections, toxins, and autoimmune inflammation. A common feature of all fibrotic diseases is the activation of ECM-producing myofibroblasts, which are key mediators of fibrotic tissue remodeling. Innate immunity plays a critical role in triggering fibrosis, with platelets and damaged epithelial and endothelial cells releasing chemotactic factors that recruit inflammatory cells. The coagulation response is the first wound-healing mechanism activated after injury, and disturbances in the coagulation cascade can lead to fibrosis. Inflammatory myeloid cells, such as macrophages and neutrophils, contribute to fibrosis by secreting toxic mediators and promoting ECM synthesis. Innate inflammatory mediators, including TNF-α and IL-1β, have been identified as important targets for antifibrotic therapy. TGF-β1 has both anti-inflammatory and profibrotic activities, and its signaling pathway is a key driver of fibrosis. M2 macrophages, alternatively activated macrophages, have been implicated in the suppression of fibrosis. Other innate myeloid-lineage cells, such as mast cells, eosinophils, and basophils, also contribute to fibrosis in multiple organ systems. Adaptive immunity, particularly T helper 17 (Th17) and T helper 2 (Th2) cells, plays a significant role in fibrosis. Th17 cells produce IL-17A, which promotes fibrosis by exacerbating inflammation and activating fibroblasts. Th2 cells produce IL-4, IL-5, and IL-13, which are key drivers of fibrosis. T regulatory (Treg) cells can either suppress or promote fibrosis, depending on their context. Intrinsic, autocrine, and epigenetic mechanisms regulate fibrosis by maintaining the activation of key fibrogenic pathways. Mechanical modifications to the ECM and cell-intrinsic changes in fibroblasts and epithelial cells contribute to fibrosis by maintaining the activation of fibrogenic pathways. The Wnt-β-catenin signaling pathway is constitutively activated in fibrotic diseases and is a potential therapeutic target. Epigenetic modifications in fibroblasts also contribute to fibrosisFibrosis is a pathological feature of most chronic inflammatory diseases, characterized by the excessive accumulation of extracellular matrix components, leading to organ dysfunction and death. It affects nearly every tissue in the body and is driven by key components of the innate and adaptive immune response, including the activation of ECM-producing myofibroblasts. Fibrosis is a major pathological feature of many chronic autoimmune diseases and influences tumor invasion, chronic graft rejection, and progressive myopathies. Despite increasing recognition of fibrosis as a major cause of morbidity and mortality in chronic inflammatory diseases, few treatments specifically target fibrosis pathogenesis. Fibrotic diseases are triggered by various factors, including genetic disorders, infections, toxins, and autoimmune inflammation. A common feature of all fibrotic diseases is the activation of ECM-producing myofibroblasts, which are key mediators of fibrotic tissue remodeling. Innate immunity plays a critical role in triggering fibrosis, with platelets and damaged epithelial and endothelial cells releasing chemotactic factors that recruit inflammatory cells. The coagulation response is the first wound-healing mechanism activated after injury, and disturbances in the coagulation cascade can lead to fibrosis. Inflammatory myeloid cells, such as macrophages and neutrophils, contribute to fibrosis by secreting toxic mediators and promoting ECM synthesis. Innate inflammatory mediators, including TNF-α and IL-1β, have been identified as important targets for antifibrotic therapy. TGF-β1 has both anti-inflammatory and profibrotic activities, and its signaling pathway is a key driver of fibrosis. M2 macrophages, alternatively activated macrophages, have been implicated in the suppression of fibrosis. Other innate myeloid-lineage cells, such as mast cells, eosinophils, and basophils, also contribute to fibrosis in multiple organ systems. Adaptive immunity, particularly T helper 17 (Th17) and T helper 2 (Th2) cells, plays a significant role in fibrosis. Th17 cells produce IL-17A, which promotes fibrosis by exacerbating inflammation and activating fibroblasts. Th2 cells produce IL-4, IL-5, and IL-13, which are key drivers of fibrosis. T regulatory (Treg) cells can either suppress or promote fibrosis, depending on their context. Intrinsic, autocrine, and epigenetic mechanisms regulate fibrosis by maintaining the activation of key fibrogenic pathways. Mechanical modifications to the ECM and cell-intrinsic changes in fibroblasts and epithelial cells contribute to fibrosis by maintaining the activation of fibrogenic pathways. The Wnt-β-catenin signaling pathway is constitutively activated in fibrotic diseases and is a potential therapeutic target. Epigenetic modifications in fibroblasts also contribute to fibrosis