Based on a multitude of clinical studies, C-reactive protein (CRP) has emerged as a risk marker for the development of cardiovascular disease, leading to recently published recommendations for screening the general population for plasma CRP level as a predictor for future cardiovascular events. However, uncertainties exist in how to apply these recommendations to populations with very high serum CRP levels and a high prevalence of cardiovascular disease, such as patients with end-stage renal disease. Furthermore, in vitro results are conflicting concerning the role of CRP in the vessel wall. Although many data are in favor of a proinflammatory effect of CRP, evidence is accumulating that CRP also exerts anti-inflammatory actions, mainly in neutrophils and platelets. Many of the apparently contradictory actions of CRP may be attributed to method issues, but, of interest, also may be explained by the existence of 2 distinct conformations of CRP, the native pentamer (nCRP) and modified CRP (mCRP) forms. nCRP is the classical acute-phase reactant detected in serum, whereas mCRP represents a predominantly tissue-bound form. It is detected immunohistochemically, mainly in and around endothelial and vascular smooth muscle cells. Although mCRP activates endothelial cells and neutrophils, induces neutrophil adhesion to the endothelium, and delays apoptosis of neutrophils in vitro, these effects were absent using nCRP. Clearly defined CRP conformers thus may provide a tool for how to reconcile the reported proinflammatory and anti-inflammatory properties of CRP. There is good evidence to believe that CRP is more than just a "bad guy," and further experiments are needed to determine how these 2 configurations contribute to atherogenesis, development of cardiovascular disease, and acute coronary events.