Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a vascular-specific inflammatory marker. It is so named because of its association with low-density lipoprotein in plasma. Atherosclerosis is an inflammatory disease. Lp-PLA2 is recognized as a risk marker in primary or secondary prevention of atherosclerosis. Elevated Lp-PLA2 levels are associated with the increased risk for cardiovascular events, even after multivariable adjustment for traditional risk factors. Patients with dyslipidemia are shown to benefit largely from the modification of Lp-PLA2. The degree of coronary artery disease (0-, 1-, 2-, or 3-vessel disease) and plasma low-density lipoprotein cholesterol significantly correlated to Lp-PLA2 levels. The low biologic fluctuation and high vascular specificity of Lp-PLA2 make it possible to use a single measurement in clinical decision making, and it also permits clinicians to follow the Lp-PLA2 marker serially. Simvastatin significantly reduces macrophage content, lipid retention, and the intima to media ratio but increased the content of smooth muscle cells in atherosclerotic lesions. Statin treatment markedly reduced Lp-PLA2 in both plasma and atherosclerotic plaques with attenuation of the local inflammatory response and improved plaque stability due to reduced inflammation and decreased apoptosis of macrophages. Darapladib, an inhibitor of Lp-PLA2 when added to lipid-lowering therapy such as statins, offers great benefit in the reduction of plaque formation. This article explores the atherosclerotic process at molecular level, role of Lp-PLA2 in atherosclerosis, the effect of lipid-lowering drugs on Lp-PLA2, effect of direct Lp-PLA2 inhibitor darapladib in the atherosclerosis process, the therapeutic implications of Lp-PLA2 as risk marker, and finally the net effect on plaque stabilization.