Axons, their ensheathing myelin and supporting glia that make up the white matter in the mammalian brain and spinal cord are fundamentally important for the normal operation of the central nervous system. Prevalent human disorders such as stroke, vascular dementia, multiple sclerosis, brain and spinal cord trauma, HIV-associated dementia, periventricular leukomalacia of premature infants, and seemingly traditional 'gray matter disorders' such as Alzheimer's disease and schizophrenia, exhibit white matter pathology that contributes to morbidity and mortality. N-Methyl-D-aspartate (NMDA) receptors have been shown to have an important role in mediating Ca2+-dependent injury of oligodendrocytes and the myelin sheath; newly recognized family members of the NMDA receptor, known as NR3 subunits, seem to be involved. Recently developed uncompetitive NMDA channel blockers such as memantine hold therapeutic promise because these agents are well tolerated clinically and might prove to be effective at protecting certain white matter elements from a variety of insults.