The phospholipase A2 enzymes are important components of the cellular machinery that responds to inflammatory stimuli and maintains cell homeostasis by membrane remodelling. Their role as the rate-limiting step in the production of pro-inflammatory lipid mediators makes these enzymes an important therapeutic target for the treatment of inflammatory disorders. Keith Glaser and colleagues explain how the two major groups of phospholipase A2, the secretory and cytosolic forms, are very different both structurally and enzymatically. Understanding the relative contributions of these different forms of phospholipase A2 to physiological and pathological conditions requires greater insight into their cellular regulation and the development of selective inhibitors.