Myocardial infarction often occurs among persons without traditional risk factors, and it has been hypothesized that assessment of "novel" markers may help identify persons who are prone to premature atherothrombosis. However, when considering the clinical utility of screening for any new marker for cardiovascular disease, physicians should consider whether there is a standardized and reproducible assay for the marker of interest; whether there is a consistent series of prospective epidemiologic studies indicating that baseline elevations of the novel marker predict future risk; and whether assessment of the novel marker adds to the predictive value of other plasma-based risk factors, specifically, the ratio of total cholesterol to high-density lipoprotein cholesterol. In this article, these criteria are used to evaluate five promising markers of cardiovascular risk: lipoprotein(a), total plasma homocysteine, fibrinolytic capacity, fibrinogen, and high-sensitivity C-reactive protein. Background is also provided to assist physicians in deciding whether one or more of these novel markers deserve clinical consideration in general outpatient settings.