A large body of literature supports the idea that inflammation plays a pivotal role in all phases of atherosclerosis, from the fatty streak lesion formation to the acute coronary event due to vulnerable plaque rupture. Indeed, vascular inflammation contributes to the pathogenesis of atherosclerosis, and later in the disease process, it is a major determinant for the acute coronary syndromes. There are various inflammatory markers that have been shown to predict cardiovascular events. These include high-sensitivity C-reactive protein (hs-CRP), a simple downstream marker of inflammation, recently emerged as a major cardiovascular risk factor. Elevated baseline concentrations of hs-CRP are associated with the risk of atherosclerotic events in general populations and show a predictive value even in terms of secondary prevention, both in patients with chronic stable angina and acute coronary syndromes. In recent year, a lot of concerns have emerged about the experimental models used to study the role of CRP in atherosclerosis; moreover, the results of trials evaluating the clinical association between this molecules and outcome are still controversial. In this paper, we attempt to review the pathophysiological evidences about the link between CRP and atherosclerosis and, most notably, about its utility as a marker and risk predictor in various clinical settings. The identification of specific triggers and mechanisms of underlying inflammation and a better understanding of each step involved in this complex process might lead to new ways to manage patients with atherosclerosis, both in terms of primary and secondary prevention, and CRP still appears to be a suitable candidate for this purpose.