Cardiovascular disease (CVD) is the major cause of mortality in individuals with diabetes mellitus. However the molecular and cellular mechanisms that predispose individuals with diabetes to the development and progression of atherosclerosis, the underlying cause of most CVD, are not understood. This paper summarizes the current state of our knowledge of pathways and mechanisms that may link diabetes and hyperglycemia to atherogenesis. We highlight recent work from our lab, and others', that supports a role for ER stress in these processes. The continued investigation of existing pathways, linking hyperglycemia and diabetes mellitus to atherosclerosis, and the identification of novel mechanisms and targets will be important to the development of new and effective antiatherosclerotic therapies tailored to individuals with diabetes.