There is substantial interest in identifying new risk factors for cardiovascular disease, to improve our understanding of disease biology and to account for the cases of heart disease that cannot be explained by known risk factors. Investigation of putative risk factors frequently involves the study of circulating biomarkers. In recent years, a spirited debate has arisen regarding the validity and usefulness of these new measures. A careful assessment of the evidence suggests that most newer biomarkers are not ready for routine clinical use in the primary prevention setting. The good news is that traditional risk factors perform quite well with regard to the prediction of future cardiovascular risk. Inadequate recognition and control of the 'classic' risk factors continues to account for a large number of avoidable cardiovascular events. At the same time, new insights into disease mechanisms should lead to the development of novel preventive therapies, regardless of how well biomarkers themselves perform in risk stratification. Furthermore, state-of-the-art technologies that allow the profiling of large panels of genes, transcripts, proteins, or small molecules should facilitate the discovery of newer biomarkers capable of providing both mechanistic insight and true prognostic utility.