As a growing number of patients with low low-density lipoprotein cholesterol levels are diagnosed with atherosclerosis, research has shifted toward markers of inflammation in an attempt to improve global cardiovascular risk prediction. These markers include cytokines, cell adhesion molecules, and acute phase reactants like high sensitivity C-reactive protein, an innate immune response protein. When measured with new high-sensitivity assays, levels of high sensitivity C-reactive protein have proven to predict future cardiovascular risk at all levels of low-density lipoprotein cholesterol, at all levels of the Framingham Risk Score, and at all levels of the metabolic syndrome. Among apparently healthy men and women, levels of high sensitivity C-reactive protein of <1, 1-3, and >3 mg/L distinguish between those at low, moderate, and high risk for future cardiovascular disease, respectively. In clinical practice, high sensitivity C-reactive protein should be used along with lipid evaluation as part of global risk assessment. Improved knowledge of cardiovascular risk should lead to improved compliance with both lifestyle and pharmacologic interventions designed to prevent future cardiovascular events.