Certain members of the phospholipase A₂ superfamily of enzymes have established causal involvement in atherosclerosis, thus at least two groups of this family of enzymes have been considered potential candidates for the prevention of cardiovascular events. Recently completed experimental animal studies, human biomarker data, vascular imaging studies, and genome-wide atherosclerosis studies provide the rationale for proceeding with clinical outcome trials directed at inhibition of secretory phospholipase A₂ and lipoprotein-associated phospholipase A₂. A clinical trial with the sPLA₂ inhibitor varespladib methyl was recently terminated, while clinical trials with the Lp-PLA₂ inhibitor darapladib are being conducted in coronary heart disease patients. This article reviews the available experimental animal and human trial evidence that serve as the basis for the development of these two classes of phospholipase A₂ inhibitors.