Most diabetes-related complications and causes of death arise from cardiovascular disease and end-stage renal disease. Amongst the major complications of diabetes mellitus are retinopathy, neuropathy, nephropathy and accelerated atherosclerosis. Increased bioavailability of reactive oxygen species (ROS) (termed oxidative stress), derived in large part from the NADPH oxidase (Nox) family of free radical producing enzymes, has been demonstrated in experimental and clinical diabetes and has been implicated in the cardiovascular and renal complications of diabetes. The present review focuses on the role of Noxs and oxidative stress in some major complications of diabetes, including nephropathy, retinopathy and atherosclerosis. We also discuss Nox isoforms as potential targets for therapy.