Although free radicals have been suggested to contribute to ischemic brain damage for more than 10 years, it is not until quite recently that convincing evidence has been presented for their involvement in both sustained and transient ischemia. The hypothesis is examined against current knowledge of free radical chemistry, as it applies to biological systems, and of cellular iron metabolism. It is emphasized that those advents have changed our outlook on free radical-induced tissue damage. First, it has been realized that damage to DNA and proteins may be an earlier event than lipid peroxidation, perhaps also a more important one. Second, evidence now exists that the triggering event in free radical-induced damage is a disturbance of cellular iron metabolism, notably delocalization of protein-bound iron, and its chelation by compounds that trigger site-specific free radical damage. Third, methods have been developed that allow the demonstration of partially induced oxygen species in tissues, and scavengers have become available that can curb free radical reactions. As a result of these events, it has been possible to demonstrate formation of free radicals in oxygen toxicity, trauma, and ischemia, and their participation in the cell damage that is incurred in these conditions, particularly in causing vascular pathology and edema. It is suggested that in ischemia, free radical damage becomes pathogenetically important when the ischemia is of long duration, when conditions favor continued delivery of some oxygen to the ischemic tissue, and particularly when such partially oxygen-deprived tissue is reoxygenated.