Renal fibrosis, particularly tubulointerstitial fibrosis, is the common final outcome of almost all progressive chronic kidney diseases. It is a reliable predictor of prognosis and a major determinant of renal insufficiency. Regardless of the initial causes, renal fibrogenesis is a dynamic and converging process consisting of four overlapping phases: priming, activation, execution, and progression. Nonresolving inflammation after sustained injury sets up the fibrogenic stage, triggering the activation and expansion of matrix-producing cells. Matrix-producing cells assemble a multicomponent, integrin-associated protein complex that integrates fibrogenic signals and orchestrates matrix production. Multiple cellular and molecular events promote scar formation and ensure a vicious progression to end-stage kidney failure. This review outlines current understanding of the cellular and molecular mechanisms of renal fibrosis, which could offer novel insights into new therapeutic strategies. Inflammation plays a critical role in the initiation and progression of renal fibrosis. Inflammatory cells, including lymphocytes, macrophages, and dendritic cells, contribute to fibrogenesis. Activation of inflammatory cells produces molecules that damage tissues and induce fibrogenic cytokines and growth factors. These events build sustained profibrotic cytokine pressure, priming fibroblasts and tubular epithelial cells to undergo phenotypic activation and produce ECM components. Inflammation also contributes to the progression of fibrosis by creating a vicious cycle of inflammation, tissue damage, and fibrosis. Activation of matrix-producing cells, such as fibroblasts, pericytes, and tubular epithelial cells, is a central event in renal fibrogenesis. Fibroblasts are the principal matrix-producing cells that generate interstitial matrix components. Activated fibroblasts express α-smooth muscle actin (αSMA) and are referred to as myofibroblasts. Myofibroblasts can originate from interstitial fibroblasts, pericytes, or tubular epithelial cells undergoing epithelial-mesenchymal transition (EMT). EMT is a cell phenotypic conversion process that occurs during embryonic development, tumor metastasis, and organ fibrosis. EMT contributes to fibrosis by promoting fibroblast migration and renal fibrosis. Recruitment of circulating fibrocytes is another source of matrix-producing cells. Fibrocytes are bone marrow-derived, circulating monocytes with fibroblast-like features. They express certain chemokine receptors and can be recruited to the injured kidney. Fibrocytes contribute to fibrogenesis by differentiating into myofibroblasts. The relative importance of fibrocytes in renal fibrogenesis is controversial, as specific markers for these cells are lacking. The assembly of fibrogenic molecular machinery involves the expression and synthesis of ECM proteins by matrix-producing cells. Key fibrogenic factors include TGF-β1, PDGF, FGF2, CTGF,Renal fibrosis, particularly tubulointerstitial fibrosis, is the common final outcome of almost all progressive chronic kidney diseases. It is a reliable predictor of prognosis and a major determinant of renal insufficiency. Regardless of the initial causes, renal fibrogenesis is a dynamic and converging process consisting of four overlapping phases: priming, activation, execution, and progression. Nonresolving inflammation after sustained injury sets up the fibrogenic stage, triggering the activation and expansion of matrix-producing cells. Matrix-producing cells assemble a multicomponent, integrin-associated protein complex that integrates fibrogenic signals and orchestrates matrix production. Multiple cellular and molecular events promote scar formation and ensure a vicious progression to end-stage kidney failure. This review outlines current understanding of the cellular and molecular mechanisms of renal fibrosis, which could offer novel insights into new therapeutic strategies. Inflammation plays a critical role in the initiation and progression of renal fibrosis. Inflammatory cells, including lymphocytes, macrophages, and dendritic cells, contribute to fibrogenesis. Activation of inflammatory cells produces molecules that damage tissues and induce fibrogenic cytokines and growth factors. These events build sustained profibrotic cytokine pressure, priming fibroblasts and tubular epithelial cells to undergo phenotypic activation and produce ECM components. Inflammation also contributes to the progression of fibrosis by creating a vicious cycle of inflammation, tissue damage, and fibrosis. Activation of matrix-producing cells, such as fibroblasts, pericytes, and tubular epithelial cells, is a central event in renal fibrogenesis. Fibroblasts are the principal matrix-producing cells that generate interstitial matrix components. Activated fibroblasts express α-smooth muscle actin (αSMA) and are referred to as myofibroblasts. Myofibroblasts can originate from interstitial fibroblasts, pericytes, or tubular epithelial cells undergoing epithelial-mesenchymal transition (EMT). EMT is a cell phenotypic conversion process that occurs during embryonic development, tumor metastasis, and organ fibrosis. EMT contributes to fibrosis by promoting fibroblast migration and renal fibrosis. Recruitment of circulating fibrocytes is another source of matrix-producing cells. Fibrocytes are bone marrow-derived, circulating monocytes with fibroblast-like features. They express certain chemokine receptors and can be recruited to the injured kidney. Fibrocytes contribute to fibrogenesis by differentiating into myofibroblasts. The relative importance of fibrocytes in renal fibrogenesis is controversial, as specific markers for these cells are lacking. The assembly of fibrogenic molecular machinery involves the expression and synthesis of ECM proteins by matrix-producing cells. Key fibrogenic factors include TGF-β1, PDGF, FGF2, CTGF,