Mammalian cells contain several calcium-independent phospholipase A 2 (PLA 2 ) enzymes. The best studied of them is the so-called Group VIA PLA 2 (iPLA 2 -VIA), which is an 85-88 kDa enzyme with unique structural features among the PLA 2 superfamily of enzymes, and has been found to play a key role in homeostatic membrane phospholipid metabolism in various cell types. Growing evidence suggests that, in addition to its homeostatic function, iPLA 2 -VIA may also play distinct roles in cellular signaling. This review focuses on the biochemical mechanisms that regulate the activity of iPLA 2 -VIA in activated cells, and the biological functions proposed for this enzyme during stimulus-response coupling.