The major risk factors of diabetic retinopathy are hyperglycemia, duration of diabetes, hypertension, and hyperlipidemia. However, it is extremely rare to develop the early pathologies of diabetic retinopathy without hyperglycemia. The pathogenesis of diabetic retinopathy is dependent on the stages of the disease and it is very clear that excessive production of VEGF (Vascular Endothelial Growth Factor) in the retina due to loss of capillaries with subsequent hypoxia is the major cause of proliferative diabetic retinopathy (PDR) and a significant of portion of people who have diabetic macular edema. The role of VEGF in causing PDR and macular edema has been substantiated by successfully using vitreous injection of anti-VEGF therapies. However, the mechanism for the cause of early changes of DR and a significant portion of macular edema are still unclear although multiple mechanisms such as oxidative stress, local inflammation, glycated products (AGE’s) and protein kinase-C activation are still being considered. Recent studies have shifted the focus from risk factors to protective factors in the retina due to clinical reports that large number of people with type 1 diabetes with duration of 50 years or longer are protected from development of severe DR even in the presence of hyperglycemia for extreme long durations. The presence of these protective factors are now being investigated and identified as potential therapies for early DR and diabetic macular edema.