Macular edema represents the end-stage of multiple pathophysiological pathways in a multitude of ocular vascular, inflammatory, and other diseases. The rationale for clinical treatment of macular edema is based on the understanding and the inhibition of these pathophysiological mechanisms. When macular edema is caused by a generalized health problem such as diabetes, high blood pressure, or generalized inflammatory conditions, treatment of these generalized diseases can in many cases cure macular edema directly. In ocular diseases, the local exudation of fluid from blood vessels is governed by Starling's law as well as by intricate cellular mechanisms linked to the tight junctions in the inner and outer blood-retinal barrier. Drugs used in clinical practice, such as nonsteroidal anti-inflammatory drugs, corticosteroids, carbonic anhydrase inhibitors, and anti-vascular endothelial growth factor agents, all act in one way or another through these cellular mechanisms. Novel treatments such as neuroprotective agents like nerve growth factors, somatostatins and antiapoptotic agents like calpain, the glutamate blocker memantine, and different caspase inhibitors may in the future inhibit neuronal cell death in the retina by separate pathways. Using dimmed nocturnal illumination may be an additional novel method to reduce hypoxic stress during dark adaptation of the rod photoreceptors in diabetes. Successful surgical treatment of macular edema using vitrectomy and peeling relies, apart from the evident release of vitreomacular traction, on many other cellular and biochemical mechanisms activated by the surgery such as oxygenation of the inner retina, removal of the posterior hyaloid as a growth factor sink, and possible Müller cell remodeling with fluid redirection after internal limiting membrane peeling.