Metabolic control alone does not predict an individual’s risk for diabetic complications. Family studies suggest that genetic factors play an important role in the predisposition for a specific type of complication and its progression. In addition to more classic genetics, research in this area has expanded to epigenetics and non-coding RNA. Epigenetic marks include modifications to the DNA or chromatin that do not change the underlying DNA sequence and may contribute to metabolic memory, the observation that the level of prior glucose control has persistent effects on the risk of complications. The elucidation of epigenetic mechanisms has the potential to identify novel therapeutic targets. Small regulatory RNAs, such as microRNAs (miRNAs), are accepted regulators of mammalian cell phenotype, and have been implicated in the regulation of biological functions associated with diabetes pathogenesis, such as metabolism, insulin secretion, and the immune response. Patterns of miRNA in various cells and tissues may provide useful disease biomarkers, while in vivo manipulation of specific subsets of small regulatory RNAs might be used for novel therapeutic strategies. What are the genes that predispose or protect people from developing diabetic nephropathy? How do candidate genes identified by genome-wide studies contribute to the pathogenesis of diabetic nephropathy? How do epigenetic mechanisms fit within the context of other known cellular mechanisms? Are epigenetic changes in chromatin responsible for metabolic memory? How do they interact with other persistent effects of glucose control, such as glycation and oxidation of long-lived macromolecules? How do persistently high fasting blood sugars or high 2 hour post-prandial blood glucose affect the miRNA of the cells? Will aggressive treatment of blood glucose reverse these destructive mechanisms? What is the role of small regulatory RNA, in particular microRNA, in the development of diabetes nephropathy? Genetic studies are particularly valuable when combined with careful phenotyping. Given the greater risk of kidney disease in African Americans and other minority groups, should GWA studies be performed in specific at-risk populations?