Hepatocyte growth factor (HGF) and its specific c-met receptor constitute a paired signaling system that plays an important role in renal development and in the maintenance of normal adult kidney structure and functions. HGF elicits potent mitogenic, motogenic, morphogenic, and antiapoptotic activities in renal tubular epithelial cells. The nature of these pleiotropic actions renders it to be specifically suited to preserve and to reconstitute the structural and functional integrity of renal tubules after acute renal injury. Emerging evidence also indicates that both endogenous and exogenous HGF are beneficial by inhibiting the onset and progression of chronic renal diseases in various animal models. Administration of exogenous HGF protein, or its gene, effectively inhibits the activation of matrix-producing myofibroblasts, attenuates extracellular matrix deposition and interstitial fibrosis, and suppresses profibrogenic cytokine transforming growth factor-β1 and its type I receptor expression in vivo. Hence, although more studies are warranted to further clarify its role in various chronic renal fibrosis models, delivery of either HGF or its gene may hold promise as a novel therapeutic strategy for promoting initial protection and subsequently regenerative repair after acute insult, and for ameliorating renal fibrosis and kidney dysfunction in chronically diseased conditions.