Diabetic retinopathy (DR) and diabetic macular edema (DME) are major causes for visual loss in adults. Nearly half of the world’s population with diabetes has some degree of DR, and DME is a major cause of visual impairment in these patients. Severe vision loss occurs because of tractional retinal detachment due to retinal neovascularization, but the most common cause of moderate vision loss occurs in DME where excessive vascular permeability leads to the exudation and accumulation of extracellular fluid and proteins in the macula. Metabolic control stands as an effective mean for controlling retinal vascular alterations in some but not all patients with diabetes, and the search of other modifiable factors affecting the risk for diabetic microvascular complications is warranted. Prolactin (PRL) and its proteolytic fragment, vasoinhibin, have emerged as endogenous regulators of retinal blood vessels. PRL acquires antiangiogenic and anti-vasopermeability properties after undergoing proteolytic cleavage to vasoinhibin, which helps restrict the vascularization of ocular organs and, upon disruption, promotes retinal vascular alterations characteristic of DR and DME. Evidence is linking PRL (and other pituitary hormones) and vasoinhibin to DR and recent preclinical and clinical evidence supports their translation into novel therapeutic approaches.