Diabetic nephropathy is characterized by glomerular basement membrane thickening and mesangial expansion. Immunohistochemical studies of diabetic kidneys showed an increased collagen type IV synthesis and deposition in the mesangial matrix, while the glomerular heparan sulfate proteoglycan content was decreased. In nodular glomerulosclerosis massive deposition of collagens III and VI appears, possibly indicating irreversibility of the pathological process. These structural changes seem to be the underlying cause for the alterations of renal functions like persistent albuminuria and proteinura. In a recent study significant glomerular infiltration by macrophages at all stages of glomerulosclerosis was observed. The pathogenesis of the multitude of cellular, structural, and functional abnormalities in diabetic nephropathy is likely to be multifactorial, involving chronic hyperglycemia as well as genetic determinants. In vitro studies with cultured glomerular cells have indicated that hyperglycemia induces transforming growth factor beta, a matrix-producing cytokine. The hyperglycemia-induced cytokine production may involve protein kinase C activation and/or the formation of advanced glucosylation end products. The elucidation of the pathogenesis of diabetic nephropathy may suggest new ways for therapeutic interventions.