Diabetic subjects are at a greater risk of developing major vascular complications due to abnormalities pertinent to the diabetic milieu. Current treatment options achieve significant improvements in glucose levels and blood pressure control, but do not necessarily prevent or retard diabetes-mediated macrovascular disease. In this review, we highlight several pathways that are increasingly being appreciated as playing a significant role in diabetic vascular injury. We focus particularly on the advanced glycation end product/receptor for advanced glycation end product (AGE/RAGE) axis and its interplay with the nuclear protein HMGB1. We discuss evidence implicating a significant role for the renin-angiotensin system, urotensin II and PPAR, as well as the importance of proinflammatory mediators and oxidative stress in cardiovascular complications. The specific targeting of these pathways may lead to novel therapies to reduce the burden of diabetic vascular complications.