With the rising epidemic of type 2 diabetes worldwide, including the United States, the death and disability due to the suboptimal control of cardiovascular disease associated with this epidemic has made prevention of type 2 diabetes emerge as a primary strategic intervention. Several modalities have been assessed in large randomized controlled trials for diabetes prevention such as lifestyle interventions and various pharmacologic agents. Included in these agents are metformin, thiazolidinediones, acarbose, angiotensin converting enzyme inhibitors, as well as angiotensin receptor blockers. Abrogation of oxidative stress appears to be a common soil hypothesis that explains the favorable effects of these agents on glucose metabolism, including the prevention of diabetes and its complications. This comprehensive review highlights the role of oxidative stress in the pathogenesis of diabetes, with emphasis on the major clinical trials conducted on prevention of type 2 diabetes.