This review article, authored by Francesco Paneni, Joshua A. Beckman, Mark A. Creager, and Francesco Cosentino, focuses on the pathophysiological mechanisms of diabetic vascular disease. It highlights the key roles of hyperglycemia and insulin resistance in the development of atherosclerosis and its complications. The authors discuss how metabolic abnormalities lead to increased production of reactive oxygen species (ROS), which, in turn, cause endothelial dysfunction and inflammation, ultimately precipitating diabetic vascular disease. The review also covers emerging topics such as the role of the endothelium in obesity-induced insulin resistance, the impact of hyperglycemia on microRNA regulation and vascular repair, alterations in coagulation and platelet reactivity, and epigenetic changes driving ROS-generating and pro-inflammatory gene expression. These insights suggest that targeted therapeutic strategies based on understanding these mechanisms may offer promising approaches to prevent cardiovascular complications in diabetes.This review article, authored by Francesco Paneni, Joshua A. Beckman, Mark A. Creager, and Francesco Cosentino, focuses on the pathophysiological mechanisms of diabetic vascular disease. It highlights the key roles of hyperglycemia and insulin resistance in the development of atherosclerosis and its complications. The authors discuss how metabolic abnormalities lead to increased production of reactive oxygen species (ROS), which, in turn, cause endothelial dysfunction and inflammation, ultimately precipitating diabetic vascular disease. The review also covers emerging topics such as the role of the endothelium in obesity-induced insulin resistance, the impact of hyperglycemia on microRNA regulation and vascular repair, alterations in coagulation and platelet reactivity, and epigenetic changes driving ROS-generating and pro-inflammatory gene expression. These insights suggest that targeted therapeutic strategies based on understanding these mechanisms may offer promising approaches to prevent cardiovascular complications in diabetes.