Diabetic retinopathy(DR), the most common ocular complication of diabetes, is one of the major causes of vision impairment and even blindness among the working population as well as middle-aged and elderly individuals. In the diabetic microvascular system, hyperglycemia damages retinal endothelial cells, enhances vascular permeability and disrupts the blood-retinal barrier through different mechanisms, all of which result in endothelial dysfunction. Retinal vascular dysfunction caused by multifactors, such as peroxisome proliferator-activated receptor-y disruption, oxidative stress, inflammation, increased advanced glycation end products and their receptors, and microRNA dysregulation can cause vascular endothelial damage, accelerate retinal endothelial dysfunction, lead to the progression of DR. Therefore, the available date and the contributors in the pathophysiology of DR are reviewed with a special emphasis on the retinal endothelial dysfunction, for a better understanding of the molecular cellular mechanism in the development of DR, to analyze the challenges in the treatment of DR and to provide new ideas and strategies for the clinical management and treatment of DR.