Circulating concentration and activity of secretory phospholipase A₂ (sPLA₂) and lipoprotein-associated phospholipase A₂ (Lp-PLA₂) have been proven as biomarkers of increased risk of atherosclerosis-related cardiovascular disease (ASCVD). Lp-PLA₂ might be part of the atherosclerotic process and may contribute to plaque destabilisation through inflammatory activity within atherosclerotic lesions. However, all attempts to translate the inhibition of phospholipase into clinically beneficial ASCVD risk reduction, including in randomised studies, by either non-specific inhibition of sPLA₂ (by varespladib) or specific Lp-PLA₂ inhibition by darapladib, unexpectedly failed. This gives us a strong imperative to continue research aimed at a better understanding of how Lp-PLA₂ and sPLA₂ regulate vascular inflammation and atherosclerotic plaque development. From the clinical viewpoint there is a need to establish and validate the existing and emerging novel anti-inflammatory therapeutic strategies to fight against ASCVD development, by using potentially better animal models and differently designed clinical trials in humans.