Several new PLA₂s have been identified based on their nucleotide gene sequences. They were classified mainly into three groups: cytosolic PLA₂ (cPLA₂), secretary PLA₂ (sPLA₂), and intracellular PLA₂ (iPLA₂). They differ from each other in terms of substrate specificity, Ca²⁺ requirement and lipid modification. The questions that still remain to be addressed are the subcellular localization and differential regulation of the isoforms in various cell types and under different physiological conditions. It is required to identify the downstream events that occur upon PLA₂ activation, particularly target protein or metabolic pathway for liberated arachidonic acid or other fatty acids. Understanding the same will greatly help in the development of potent and specific pharmacological modulators that can be used for basic research and clinical applications. The information of the human and other genomes of PLA₂s, combined with the use of proteomics and genetically manipulated mouse models of different diseases, will illuminate us about the specific and potentially overlapping roles of individual phospholipases as mediators of physiological and pathological processes. Hopefully, such understanding will enable the development of specific agents aimed at decreasing the potential contribution of individual secretary phospholipases to vascular diseases. The signaling cascades involved in the activation of cPLA₂ by mitogen activated protein kinases (MAPKs) is now evident. It has been demonstrated that p44 MAPK phosphorylates cPLA₂ and increases its activity in cells and tissues. The phosphorylation of cPLA₂ at ser505 occurs before the increase in intracellular Ca²⁺ that facilitate the binding of the lipid binding domain of cPLA₂ to phospholipids, promoting its translocation to cellular membranes and AA release. Recently, a negative feed back loop for cPLA₂ activation by MAPK has been proposed. If PLA₂ activation in a given model depends on PKC, PKA, cAMP, or MAPK then inhibition of these phosphorylating enzymes may alter activities of PLA₂ isoforms during cellular injury. Understanding the signaling pathways involved in the activation/deactivation of PLA₂ during cellular injury will point to key events that can be used to prevent the cellular injury. Furthermore, to date, there is limited information available regarding the regulation of iPLA₂ or sPLA₂ by these pathways.