Phospholipases A2 (PLA2) belong to a super-family of enzymes that hydrolyze membrane phospholipids at the sn-2 position to liberate free fatty acids and lysophospholipids. Different forms of PLA2 are involved in inflammation, neurodegeneration, and intracellular and intercellular signaling related to neurotransmitter release, axonal growth and gene expression. The action of cytosolic PLA2 (cPLA2) on phospholipid containing arachidonic acid at sn-2 position releases arachidonic acid and lysophospholipids, precursors for various proinflammatory lipid mediators including prostaglandins, leukotrienes, thromboxanes, and platelet activating factor. During hypoxic/ischemic insults, alterations in calcium homeostasis and induction of cytokines results in stimulation of cPLA2 and increased production of prostaglandins, leukotrienes, thromboxanes, and platelet activating factor. These metabolites cause atherosclerotic plaque development in cerebrovascular and coronary artery diseases in arterial walls and neuronal cell injury in brain tissue. Our studies on kainic acid-induced neurodegeneration in rat brain indicate that the stimulation of cPLA2 increased generation of proinflammatory lipid mediators, and accumulation of 4-hydroxynonenal, a toxic aldehyde with neurodegenerative properties. Treatment of rat brain hippocampal slices with antimalarial drugs (non-specific cPLA2 inhibitors) not only inhibits cPLA2 activity but also blocks neurodegeneration suggesting that cPLA2 inhibitors can be used as neuroprotective and anti-inflammatory agents in neurodegenerative diseases.