A review of reactive oxygen species (ROS) is followed by a discussion on the differential susceptibility of astrocytes and oligodendroglia to ischemia-related insults. Astrocytes can survive chronic hypoxia as well as long periods of simulated ischemia, i.e. hypoglycemia and anoxia. Oligodendroglia are preferentially injured over astrocytes by chronic hypoxia, reperfusion following ischemia, hypoglycemia or uncoupling of oxidative phosphorylation. Increasing the generation of ROS in mixed glial cultures by adding ROS generators results in preferential death of oligodendroglia. Oligodendroglia are more susceptible to oxidative stress because they have low glutathione contents while concomitantly having higher iron contents and are more dependent upon oxidative phosphorylation than are astrocytes. Glutathione plays a pivotal role in the ROS-scavenging strategies of the cell while iron plays a pivotal role in the generation of hydroxyl, peroxy and akoxy radicals. These in vitro findings delineate the physiological basis for the white matter damage seen in adults following prolonged periods of hypoperfusion and the damage seen in the oligodendroglial germinal zones resulting in periventricular leukomalacia seen following in utero hypoxia-ischemia.