Diabetic macular edema (DME) is the leading cause of visual loss in diabetic patients and is characterized by accumulation of extracellular fluid in the retina. The most important mechanism involved is breakdown of the blood-retinal barrier (BRB), which is likely to be due to changes of tight junction proteins, including occludin and the zonula occludens proteins. Hyperglycemia and retinal ischemia stimulate the synthesis and secretion of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). Both the aqueous humor and vitreous fluid levels of VEGF and IL-6 are significantly elevated in patients who have DME when compared with non-diabetic patients. Vascular permeability factors, including VEGF and IL-6, may act directly on endothelial cell tight junctions to decrease their protein content or increase phosphorylation. Either or both of these changes may lead to increased paracellular permeability. The specific molecules that are allowed to move through intercellular junctions may depend on the particular vascular permeability factor involved, as well as its concentration, duration of action, and interaction with other factors. Defining the molecular mechanisms of DME will be critical for the development of specific therapy.