Definitive evidence of oxygen radical-mediated lipid peroxidation as a cause of tissue injury in the setting of brain ischemia has proven elusive. We review the experimental data from our own and other laboratories on this subject. Spectroscopic detection of the conjugated diene structure, the earliest structural alteration produced by fatty acid radicalization, is an inconstant and highly focal observation in the recirculated ischemic brain. Alterations of lipid-soluble antioxidants offer an indirect indication of possible free radical reactions. Other inferences of lipid peroxidation have derived from studies of selective disappearance of free fatty acids. Recent studies of tissue conjugated diene in two rat models of thrombotic infarction with acute reperfusion yielded inconsistent evidence for lipid peroxidation, and in rats subjected to 25 min of diffuse forebrain ischemia, no evidence of conjugated diene formation was observed during early recirculation. We conclude that evolving parenchymal injury in these settings is unlikely to derive from spectroscopically observable lipid autoxidation.