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Phospholipase A2 (PLA2) are esterases that cleave glycerophospholipids to release fatty acids and lysophospholipids. Several studies demonstrate that PLA2 regulate growth and signaling in several cell types. However, few of these studies have focused on Ca2+-independent phospholipase A2 (iPLA2 or Group VI PLA2). This class of PLA2 was originally suggested to mediate phospholipid remodeling in several cell types including macrophages. As such, it was labeled as a housekeeping protein and thought not to play as significant of roles in cell growth as its older counterparts cytosolic PLA2 (cPLA2 or Group IV PLA2) and secretory PLA2 (sPLA2 or Groups I-III, V and IX-XIV PLA2). However, several recent studies demonstrate that iPLA2 mediate cell growth, and do so by participating in signal transduction pathways that include epidermal growth factor receptors (EGFR), mitogen activated protein kinases (MAPK), mdm2, and even the tumor suppressor protein p53 and the cell cycle regulator p21. The exact mechanism by which iPLA2 mediates these pathways are not known, but likely involve the generation of lipid signals such as arachidonic acid, lysophosphatidic acid (LPA) and lysophosphocholines (LPC). This review discusses the role of iPLA2 in cell growth with special emphasis placed on their role in cell signaling. The putative lipid signals involved are also discussed.