Inflammation plays a major role in the initiation and progression of coronary artery disease (CAD) and the precipitation of acute coronary events. However, the inflammatory triggers are poorly understood. Noninfectious stimuli undoubtedly play a role. Recently, chronic infection has been proposed as another inflammatory trigger. Histologically, unstable atherosclerotic plaque contains activated macrophages and T lymphocytes, adhesion molecules, chemokines and cytokines, matrix-degrading enzymes, and prothrombotic factors. Circulating inflammatory markers such as C-reactive protein, fibrinogen, and interleukins are increased in high-risk cohorts and predict future risk. Experimental models and human studies have supported a role of infection in the promotion of atherosclerosis. Although the independent predictive value of seropositivity to individual agents has varied, total pathogen burden, the sum of seropositivities to many bacterial and viral vectors, has been more consistent. Whether antibiotics or vaccines will be useful in CAD prevention remains to be shown. Meanwhile, therapies with proven vascular anti-inflammatory effects (eg, diet, exercise, smoking cessation, aspirin, statins) should be optimized.