Risk of diabetic complications continues to escalate overtime despite a multifactorial intervention with glucose-lowering drugs, anti-hypertensive agents and statins. In this perspective, a mechanisms-based therapeutic approach to vascular disease in diabetes represents a major challenge. Epigenetic signatures are emerging as important determinants of vascular disease in this setting. Methylation and acetylation of DNA and histones is a reversible process leading to dysregulation of oxidant and inflammatory genes such as mitochondrial adaptor p66(Shc) and transcription factor NF-kB p65. Epigenetic modifications associated with diabetes may contribute to the early identification of high risk individuals. Ongoing epigenomic analyses will be instrumental in identifying the epigenetic variations that are specifically associated with cardiovascular disease in patients with diabetes. Here, we describe a complex scenario of epigenetic changes and their putative link with diabetic vascular disease. Pharmacological reprogramming of diabetes-induced epigenetic signatures may be a promising option to dampen oxidative stress and inflammation, and thus prevent cardiovascular complications in this setting. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.