Diabetic retinopathy is a major complication of diabetes mellitus that can lead to retinal vascular abnormalities and visual impairment. While retinal endothelial pathology is well studied, retinal pigment epithelium (RPE) layer modifications and the patho-physiological regulations are not widely understood. The RPE is a highly specialized pigmented layer regulating not only physiological functions such as transport of nutrients, ions, absorption of light, phagocytosis of photoreceptor membranes, but also secretion of a number of cytokines, chemokines, angiogenic and anti-angiogenic factors. The RPE secretome, though crucial in health and disease, remains elusive in diabetic retinopathy. A knowledge of these secreted factors would help explain and correlate the clinical phase of the disease aiding in improved disease management. A comprehensive knowledge of the secreted factors of the RPE is a potential tool for understanding the differential treatment regime of early diabetic retinopathy, diabetic proliferative retinopathy and diabetic macular edema. In this review, we have delineated the importance of factors secreted by the retinal pigment epithelium and its regulation in the pathogenesis of diabetic retinopathy.