Diabetic maculopathy is the leading cause of visual loss in diabetic patients. The pathogenesis is not fully understood and a satisfactory therapy is currently not available. Malfunction of the blood-retinal barrier plays a central role in the disease and leads to retinal edema and secondary photoreceptor dysfunction. Diabetic vascular leakage and macular edema are regulated by a distinct combination of direct paracellular transport, alterations in endothelial intercellular junctions and endothelial cell death. The distribution and relevance of these three factors to diabetic maculopathy varies over the course of the disease. Cumulative endothelial cell death will become more relevant after prolonged diabetic conditions. This article reviews the current knowledge on the pathogenic mechanisms of diabetic macular edema.