Anti-inflammatory add-on therapy to conventional cardiovascular prophylaxis has been proposed as a novel therapeutic approach to potentially reduce residual cardiovascular risk. This hypothesis has been challenged by a series of unsuccessful Phase III studies testing the impact on clinical outcomes of novel agents with immunomodulatory actions. Specifically, the apparent ability of phospholipase A2 (PLA2) inhibitors and of antioxidants to ameliorate inflammation and to reduce coronary disease in Phase II trials did not translate into improved secondary cardiovascular prevention in larger population-based studies. Other anti-inflammatory agents are still under scrutiny. However, studies to date have lacked information on the inflammatory profile of the participants, both at baseline and at follow-up, thereby limiting the possibility of identifying subgroups of patients in whom 'residual inflammation' can be detected despite optimal conventional therapy, and who could therefore benefit from a cardiovascular prevention strategy specifically targeting inflammation. This has also rendered it difficult to interpret the results as a conclusive demonstration of inefficacy of the tested anti-inflammatory strategies in the treatment of atherosclerosis. We here discuss the importance of better patient characterization to minimize heterogeneity of the study population, so that effectiveness of different anti-inflammatory strategies can be evaluated in targeted subgroups of patients. We also illustrate how specific inflammatory biomarkers could assist in this process, with particular emphasis on the roles of high-sensitivity C-reactive protein and circulating monocyte phenotype.