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Oxygen-derived reactive species such as oxyl, peroxyl, and hydroxyl radicals are initiators of a damaging cascade of events known as oxidative stress (OS) whereby cellular macromolecules are attacked and cell damage may occur. Brain tissue is particularly vulnerable to damage, because on the one hand it has a high consumption of oxygen and contains ample radical-sensitive targets while on the other hand it is less endowed with a robust and diverse enzymatic and nonenzymatic antioxidant arsenal. Polyunsaturated fatty acids which are almost exclusively and ubiquitously found in membrane phospholipids (PL) are major radical-sensitive targets. As a result of the action of hydroxyl radicals, lipid peroxidation takes place and lipid hydroperoxides are generated. While these perturb membrane structure/function and can be deleterious to cells, they may also take part in redox reactions which may beneficially amend the harmful consequences of the injury. That may well depend on the topology of the PUFAs in the bilayer as well as on replenishment mechanisms to restore membrane integrity. Stress metabolites derived from docosahexaenoic acid (DHA, 22:6n-3) may act as neuroprotectants after being released from PL. On the other hand, lipid-bound DHA and the vinyl ether bonds of ethanol amine PLs constitute a large reservoir of endogenous metabolites which could also provide neuroprotection. In the developing brain the nutritional supply of DHA is crucial since the antioxidant cellular machinery is less developed. In the aging brain or in neurodegenerative disorders, the pronounced depletion of DHA-enriched PL may indicate a persistent oxidative catabolic degradation, unmatched by a proper reacylation of the PUFAs. Unravelling the lipidomic vocabulary of molecular species which contain DHA or are generated from DHA during development, aging, and trauma should pave the way for treating OS-related diseases. [ABSTRACT FROM AUTHOR]