Retinopathy is one of the most severe ocular complications of diabetes and is a leading cause of acquired blindness in young adults. The cellular components of the retina are highly coordinated but very susceptible to the hyperglycemic environment. The microvasculature of the retina responds to hyperglycemic milieu through a number of biochemical changes, including increased oxidative stress and polyol pathway, PKC activation and advanced glycation end product formation. Oxidative stress is considered as one of the crucial contributors in the pathogenesis of diabetic retinopathy, but oxidative stress appears to be highly interrelated with other biochemical imbalances that lead to structural and functional changes and accelerated loss of capillary cells in the retinal microvasculature and, ultimately, pathological evidence of the disease. One such potential connection that links oxidative stress to metabolic alterations is gyceraldehyde-3-phosphate dehydrogenase whose activity is impaired in diabetes, and that results in activation of other major pathways implicated in the pathogenesis of diabetic retinopathy. Alterations associated with oxidative stress offer many potential therapeutic targets making this an area of great interest to the development of safe and effective treatments for diabetic retinopathy. Animal models of diabetic retinopathy have shown beneficial effects of antioxidants on the development of retinopathy, but clinical trials (though very limited in numbers) have provided somewhat ambiguous results. Although antioxidants are being used for other chronic diseases, controlled clinical trials are warranted to investigate potential beneficial effects of antioxidants in the development of retinopathy in diabetic patients.