Excessive glutamate signaling can lead to excitotoxicity, a phenomenon whereby over-activation of glutamate receptors initiates neuronal death. In recent years, it has been shown that glutamate can be toxic to white-matter oligodendrocytes. Up to recently, the prevailing view was that oligodendrocyte excitotoxicity is mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate glutamate receptor types. Three recent studies have shown that oligodendrocytes also express N-methyl-D-aspartate (NMDA) receptors, which are activated under pathological conditions. Thus, NMDA receptors seem to be a promising target for the development of new drugs to treat white-matter damage in acute and chronic diseases.