There is compelling evidence that C-reactive protein is a sensitive marker for the development of cardiovascular disease in the general population. Recent studies suggest that C-reactive protein is not only a biomarker but also an active mediator in the pathogenesis of atherosclerosis. We review the evidence and suggest mechanisms by which C-reactive protein can damage arterial endothelium and promote the development of atherosclerotic lesions, including the effects of C-reactive protein on arterial endothelial activation, macrophage recruitment, and foam cell generation. The direct role of C-reactive protein in sustaining a proinflammatory and procoagulant milieu within the arterial neointima is emphasized. We also discuss the evidence that C-reactive protein can injure arterial endothelium. Finally, we review therapies that target C-reactive protein for primary prevention and for the treatment of atherosclerotic diseases.