Diabetic retinopathy, a common secondary complication of diabetes mellitus, involves extensive damage to the retinal microvasculature. Retina, being a susceptible target, is highly prone to hyperglycemia-induced molecular damages. PPAR receptor, chiefly gamma subtype, mediates numerous responses related to glucose metabolism and hence is utilized, through its agonism, for the restoration of normal insulin sensitivity and glucose homeostasis in the body. Although a number of synthetic PPAR-gamma receptor agonists have been developed and are being employed for treatment purposes, the role of its endogenous ligand in the prevention of diabetic retinopathy is poorly acknowledged. Activation of PPAR-gamma receptor, via endogenous agents, provides a natural defensive shield against various hyperglycemia-induced pathological conditions. Although the biological levels of 15d-PGJ2 (an endogenous agonist of PPAR-gamma receptor) are found to be below the concentration required to trigger PPAR-gamma-mediated actions, employment of several advanced methods for the exogenous administration of this ligand might provide a beneficial option. Besides, 15d-PGJ2-induced defense is better than any of the newly developed alternative therapies, such as anti-inflammatory, anti-angiogenic or anti-apoptotic agents, of diabetic retinopathy, since it singularly provides, virtually, a complete protection package against all these pathological eventualities. Therefore, the physiology of this endogenous PPAR-gamma ligand might, possibly, be exploited to a great extent for the development of prophylactic agents, in order to restrict the progression of diabetic retinopathy.