A hallmark of diabetic retinopathy is increased vascular permeability. The vasculature of the retina, which normally has tight control of the fluid and blood components that enter the retina, becomes leaky in diabetes leading to increased albumin flux into the retina, fluid accumulation, and macular edema, and over time may progress to hemorrhaging vessels. This chapter investigates our knowledge regarding the formation of the blood—brain and blood—retinal barrier. The molecular composition of the junctional complex that forms the basis of the blood—retinal barrier will be briefly reviewed and the changes that occur to the junctional complex in diabetes will be examined. Changes in permeability and the contribution of inflammatory cytokines in addition to vascular endothelial growth factor will be presented and potential therapies will be considered. It is the goal of this chapter that the reader will have a fundamental understanding of the development and structure of the blood—retinal barrier and know-ledge of our current understanding of the alterations to the junctional complex that contribute to vessel permeability in diabetic retinopathy.