This brief review describes studies in a pancreatic beta cell line and in animal models of type 2 diabetes (T2D) designed to assess the deleterious role of chronic hyperglycemia and oxidative stress in beta cell structure and function. They illustrate that beta cells are especially vulnerable to oxidative stress because of their intrinsically deficient complement of anti-oxidant enzymes, which facilitates disappearance of insulin gene transcription factors during chronic hyperglycemia. Genetic overexpression of an anti-oxidant gene, glutathione peroxidase (Gpx) and treatment with an oral GPx mimetic, Ebselen, are shown to protect diabetes-prone rats against oxidative stress with consequent preservation of beta cell structure and function. These findings suggest that clinically accepted GPx mimetics might protect against full-blown T2D if administered early in the course of the disease in humans.