This review will focus specifically on lipoprotein-associated phospholipase A2 (Lp-PLA2) and its inhibitor darapladib. Lp-PLA 2 is bound predominantly to apolipoprotein B (apoB)-containing lipoproteins and highly expressed in the necrotic core of atherosclerotic lesions. It rapidly degrades oxidatively modified phospholipids in modified LDL, for example, leading to formation of proinflammatory and cytotoxic products (i.e., lysophosphatidylcholine and oxidized nonesterified fatty acids). In a study conducted in diabetic and hypercholesterolemic swines, selective Lp-PLA2 inhibitors (i.e., darapladib) reduced the development of advanced coronary atherosclerosis. Specifically, darapladib treatment considerably decreased the area of plaques and the necrotic cores, and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. In the IBIS 2 study conducted in humans, darapladib significantly halted the increase of the necrotic core volume (-0.5 ± 13.9 mm3; P = 0.71) that was observed in the cohort receiving placebo (4.5 ± 17.9 mm3; P = 0.009), resulting in a significant treatment difference of -5.2 mm3 (P = 0.012). In conclusion, despite standard-of-care treatment, patients with coronary artery disease continue to have recurrent cardiovascular events. PLA2 inhibition may represent a new approach for the treatment of atherosclerosis if the benefit of this intervention is confirmed by the results of ongoing event-driven outcome trials. Copyright