Secretory phospholipase A2 (sPLA2) represents a class of enzymes that hydrolyze phospholipids from cellular membranes and lipoproteins, resulting in multifarious proatherogenic actions in the vessel wall. Proatherogenic actions of sPLA2 involve lipoprotein remodeling that facilitates proteoglycan binding and formation of lipid aggregates that are rapidly internalized by tissue macrophages. The hydrolysis of phospholipids on cell membranes generates bioactive lipids and lipolipoproteins with increased oxidative susceptibility. These particles and other bioactive lipids activate inflammatory pathways in various cells of the vessel wall. Transgenic mice overexpressing groups IIA, V, and X have increased atherosclerosis formation, whereas mice deficient in these sPLA2 isoenzymes have less atherosclerosis formation. In apolipoprotein E knockout mice fed an atherosclerotic diet, sPLA2 inhibition with varespladib reduced atherosclerosis formation. The potential for sPLA2 inhibitors for preventing cardiovascular events is being investigated.