The blood-retinal barrier (BRB) regulates transport across retinal capillaries maintaining proper neural homeostasis and protecting the neural tissue from potential blood borne toxicity. Loss of the BRB contributes to the pathophysiology of a number of blinding retinal diseases including diabetic retinopathy. In this review, we address the basis of the BRB, including the molecular mechanisms that regulate flux across the retinal vascular bed. The routes of transcellular and paracellular flux are described as well as alterations in these pathways in response to permeabilizing agents in diabetes. Finally, we provide information on exciting new studies that help to elucidate the process of BRB development or barriergenesis and how understanding this process may lead to new opportunities for barrier restoration in diabetic retinopathy.