Cardiovascular complications remain the leading causes of morbidity and premature mortality in patients with diabetes mellitus. Studies in humans and preclinical models demonstrate lasting gene expression changes in the vasculopathies initiated by previous exposure to high glucose concentrations and the associated overproduction of reactive oxygen species. The molecular signatures of chromatin architectures that sensitize the genome to these and other cardiometabolic risk factors of the diabetic milieu are increasingly implicated in the biological memory underlying cardiovascular complications and now widely considered as promising therapeutic targets. Atherosclerosis is a complex heterocellular disease where the contributing cell types possess distinct epigenomes shaping diverse gene expression. Although the extent that pathological chromatin changes can be manipulated in human cardiovascular disease remains to be established, the clinical applicability of epigenetic interventions will be greatly advanced by a deeper understanding of the cell type–specific roles played by writers, erasers, and readers of chromatin modifications in the diabetic vasculature. This review details a current perspective of epigenetic mechanisms of macrovascular disease in diabetes mellitus and highlights recent key descriptions of chromatinized changes associated with persistent gene expression in endothelial, smooth muscle, and circulating immune cells relevant to atherosclerosis. Furthermore, we discuss the challenges associated with pharmacological targeting of epigenetic networks to correct abnormal or deregulated gene expression as a strategy to alleviate the clinical burden of diabetic cardiovascular disease.