Although diabetic nephropathy occurs only in a minority of diabetic patients (approximately 30%), it is the major single cause of end-stage renal disease in the United States. Hyperglycemia and hypertension are important factors predisposing patients to nephropathy, however, accumulating evidence points to critical genetic factors that predispose only a subset of diabetic patients to nephropathy. Defining the genes responsible for nephropathy risk in human populations has proven challenging. Comparative genomics using the robust genetic reagents available in the laboratory mouse should provide a complementary approach to defining genes that may predispose to diabetic nephropathy in mice and human beings. In this article we review studies that have started to identify genetic risk factors for diabetic nephropathy in mice and the multiple approaches that may be used to elucidate the genetic pathogenesis of this disorder.