The kidney has unique attributes that are related to its complex structure and that affect the nature of fibrogenesis in this organ. It is divided into functional units, called nephrons, that have both a filtering and a reabsorbing component. Sclerosis may initiate in the sites of either of these components but ultimately involves both. The epidemiology and clinical manifestations of renal fibrosis suggest complex genetic and environmental influences on the development of fibrosis. Further, the different structures in the kidney manifest different mechanisms of fibrogenesis. These are determined by a combination of differences in the biology of the affected cells and the physical effects of nephron failure. Although therapy for renal fibrosis remains somewhat problematic, new insights into the mechanisms of the underlying diseases offer the promise of improved approaches to treatment.