Inflammation lies at the base of endothelial dysfunction, eventually leading to plaque formation. The degree of inflammation defines the "vulnerability" of plaque to rupture. Numerous strategies have been adopted to identify and eventually treat high-risk vulnerable plaque. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has emerged as one such candidate marker of inflammation that may play a direct role in the formation of rupture-prone plaque. Epidemiologic studies have clearly demonstrated the prognostic ability of increased Lp-PLA(2) levels and their association with increased risk of future coronary and cerebrovascular events. Moreover, Lp-PLA(2) might have similar predictive power for both incident coronary heart disease in initially healthy individuals as well as for recurrent events in those with clinically manifest atherosclerosis. The latest evidence has also suggested its incremental value for risk determination over the well-established traditional risk factors and biomarkers in patients with congestive heart failure. These data support an integral role of Lp-PLA(2) activity in lipid peroxidation and cardiovascular risk assessment. This review summarizes the current body of evidence supporting the clinical utility of Lp-PLA(2) and its future applications in cardiovascular medicine.