Oligodendrocytes, myelin-forming glial cells of the central nervous system, are vulnerable to damage in a variety of neurologic diseases. Much is known of primary myelin injury, which occurs in settings of genetic dysmyelination or demyelinating disease. There is growing awareness that oligodendrocytes are also targets of injury in acute ischemia. Recognition of oligodendrocyte damage in animal models of ischemia requires attention to their distinct histologic features or use of specific immunocytochemical markers. Like neurons, oligodendrocytes are highly sensitive to injury by oxidative stress, excitatory amino acids, trophic factor deprivation, and activation of apoptotic pathways. Understanding mechanisms of oligodendrocyte death may suggest new therapeutic strategies to preserve or restore white matter function and structure after ischemic insults.