Phospholipases A₂ (PLA2s) are esterases that hydrolyze the sn-2 ester of glycerophospholipids and constitute one of the largest families of lipid hydrolyzing enzymes. The mammalian genome contains 10 enzymatically active secreted PLA2s (sPLA2s) and two sPLA2-related proteins devoid of lipolytic enzymatic activity. In addition to the well-established functions of one of these enzymes in digestion of dietary phospholipids and another in host defense against bacterial infections, accumulating evidence shows that some of these sPLA2s are involved in arachidonic acid release from cellular phospholipids for the biosynthesis of eicosanoids, especially during inflammation. More speculative results suggest the involvement of one or more sPLA2s in promoting atherosclerosis and cancer. In addition, the mammalian genome encodes several types of sPLA2-binding proteins, and mounting evidence shows that sPLA2s may have functions related to binding to cellular target proteins in a manner independent of their lipolytic enzymatic activity.