Retinopathy, a sight-threatening disease, remains one of the most feared complications of diabetes. Although hyperglycemia is the main initiator, progression of diabetic retinopathy continues even after re-institution of normal glycemic control in diabetic patients, and the deleterious effects of prior hyperglycemic insult depend on the duration and the severity of this insult, suggesting a ‘metabolic memory’ phenomenon. Metabolic memory phenomenon is successfully duplicated in the experimental models of diabetic retinopathy. Hyperglycemia, in addition to initiating many other biochemical and functional abnormalities and altering expression of genes associated with them, also increases oxidative stress. Increased production of cytosolic reactive oxygen species dysfunctions the mitochondria, and a compromised antioxidant defense system becomes overwhelmed to neutralize free radicals. With the duration of diabetes extending, mitochondrial DNA (mtDNA) is also damaged, and transcription of mtDNA-encoded genes, important for function of the electron transport chain, is compromised. This fuels into a ‘self-propagating’ vicious cycle of free radicals, and retinopathy continues to progress. Hyperglycemic insult also affects the enzymatic machinery responsible for epigenetic modifications; these modifications alter gene expression without affecting the DNA sequence. Histones and/or DNA modifications of many enzymes, important in mitochondrial homeostasis, affect their activities and disturb mitochondrial homeostasis. Experimental models have shown that these epigenetic modifications have potential to halt only if normal glycemia is maintained from the day of induction of diabetes (streptozotocin) in rats, but if hyperglycemia is allowed to proceed even for couple months before initiation of normal glycemia, these epigenetic modification resist reversal. Supplementation of a therapy targeted to prevent increased oxidative stress or epigenetic modifications, during the normal glucose phase, which has followed high glucose insult, however, helps ameliorate these abnormalities and prevents the progression of diabetic retinopathy. Thus, without undermining the importance of tight glycemic control for a diabetic patient, supplementation of their ‘best possible’ glycemic control with such targeted therapies has potential to retard further progression of this blinding disease.