Phospholipases A2 belong to a large family of enzymes involved in the generation of several second messengers that play an important role in signal transduction processes associated with normal brain function. The phospholipase A2 family includes secretory phospholipase A2, cytosolic phospholipase A2, calcium-independent phospholipase A2, and plasmalogen-selective phospholipase A2. The systemic administration of kainic acid to rats results in seizures and subsequent degeneration of specific neurons in the hippocampus and striatum. The kainic acid-induced neurodegeneration is accompanied by upregulation of PLA2 activity and immunoreactivity. Stimulation of PLA2 activity results in the degradation of phospholipids in neuronal membranes with the generation of arachidonic acid and lysophospholipids. These products are further metabolized to potent inflammatory mediators such as eicosanoids and platelet activating factor. Although an inflammatory response can be induced by many different means, phospholipase A2-generated inflammatory mediators are closely associated with the pathogenesis of inflammation and oxidative stress in neurodegenerative diseases. Peroxidation of arachidonic acid, a PLA2 reaction product, also results in generation of 4-hydroxy-2,3-nonenal (4- HNE), an α, β-aldehyde with neurotoxic properties. In kainic acid-mediated neurotoxicity, the treatment of brain slices with antimalarial drugs, quinacrine, chloroquine, hydroxychloroquine, and quinine, inhibits neurodegeneration and reduces PLA2 and 4-HNE immunoreactivities. This suggests that antimalarial drugs can be used as neuroprotectants and anti-inflammatory agents in neurodegenerative diseases. In vitro and in vivo studies indicate that antimalarial drugs can also be used for the treatment of prion diseases, ischemic injury, and experimental Parkinson disease (PD). These drugs maintain blood pressure, decrease infarct size, reduce inflammation, and inhibit neurodegeneration in focal and global models of cerebral ischemia and protect dopaminergic neurons from neurodegeneration in experimental PD. Initial attempts to treat Creutzfeldt-Jakob disease (CJD) with quinacrine in humans indicate that this antimalarial drug may have some transient beneficial effects in advanced CJD patients. Antimalarial drugs have no beneficial effects in Alzheimer disease.