Epigenetic modifications regulate critical functions that underlie chromosome metabolism. Understanding the molecular changes to chromatin structure and the functional relationship with altered signaling pathways is now considered to represent an important conceptual challenge to explain diabetes and the phenomenon of metabolic or hyperglycemic memory. Although it remains unknown as to the specific molecular mechanisms whereby hyperglycemic memory leads to the development of diabetic vascular complications, emerging evidence now indicates that critical gene-activating epigenetic changes may confer future cell memories. Chemical modification of the H3 histone tail of lysine 4 and 9 has recently been identified with gene expression conferred by hyperglycemia. The persistence of these key epigenetic determinants in models of glycemic variability and the development of diabetic complications has been associated with these primary findings. Transient hyperglycemia promotes gene-activating epigenetic changes and signaling events critical in the development and progression of vascular complications. As for the role of specific epigenomic changes, it is postulated that further understanding enzymes involved in writing and erasing chemical changes could transform our understanding of the pathways implicated in diabetic vascular injury providing new therapeutic strategies.