Phospholipase A₂ (PLA₂) enzymes are critical regulators of prostaglandin and leukotriene synthesis and can directly modify the composition of cellular membranes,. PLA₂ enzymes release fatty acids and lysophospholipids, including the precursor of platelet-activating factor, PAF, from phospholipids. Free fatty acids, eicosanoids, lysophospholipids and PAF are potent regulators of inflammation,,, reproduction^,, and neurotoxicity,,. The physiological roles of the various forms of PLA₂ are not well defined. The cytosolic form, cPLA₂, preferentially releases arachidonic acid from phospholipids and is regulated by changes in intracellular calcium concentration,. We have now created ‘knockout’ (cPLA₂^−/−) mice that lack this enzyme, in order to evaluate its physiological importance. We find that cPLA₂^−/− mice develop normally, but that the females produce only small litters in which the pups are usually dead. Stimulated peritoneal macrophages from cPLA₂^−/− animals did not produce prostaglandin E₂ or leukotriene B₄ or C₄. After transient middle cerebral artery occlusion, cPLA₂^−/− mice had smaller infarcts and developed less brain oedema and fewer neurological deficits. Thus cPLA₂ is important for macrophage production of inflammatory mediators, fertility, and in the pathophysiology of neuronal death after transient focal cerebral ischaemia.