Diabetes mellitus is the leading cause of end-stage renal disease. Development and progression of diabetic nephropathy result from a combination of genetic susceptibility and metabolic and hemodynamic abnormalities. In America, some racial and ethnic minorities have a significant burden of diabetic nephropathy, and, although genetic studies suggest that inherited factors play a major role in the pathogenesis of diabetic nephropathy, little information has been gained on the genes and molecular mechanisms involved. The genetic background of diabetic nephropathy is believed to be polygenic, and the genes predisposing to the development and progression of diabetic nephropathy are actively being investigated. New knowledge in identifying and understanding the role of susceptibility gene(s) will provide valuable information that could help develop new preventive and therapeutic strategies.