The incidence of obesity, cardiometabolic syndrome (CMS), and type 2 diabetes mellitus (DM2), as well as their devastating cardiovascular consequences, keep rising with increasing human and economical costs. For a long time, insulin resistance has been the main player in the pathogenesis and treatment of DM2, but every day more knowledge is gained about the central role of beta-cell failure, not only in the appearance of hyperglycemia but also in the failure of the pharmacological therapy. beta-Cell failure implies impairment of glucosestimulated insulin secretion and loss of beta-cell mass. Hyperglycemia, elevated circulating fatty acids, inadequate local activation of renin angiotensin system, and chronic low grade inflammation are conditions that coexist in the CMS and DM2 that turn out to be deleterious for the beta-cell functioning and existance. Excessive oxidative stress secondary to increased production of reactive oxygen species and decreased availability of antioxidants is a possible common converging point of the multiple noxious stimuli. Activation of the NADPH oxidase complex secondary to angiotensin II stimulation is of interest, as its pharmacological blockade has beneficial effects. New knowledge about the intimate mechanisms of oxidative-stress induced beta-cell failure will provide new therapeutic targets against CMS and DM2.