The public-health impact of cardiovascular disease (CVD) remains high despite advances in prevention and treatment. Large numbers of cardiovascular events occur in asymptomatic people who do not have a high level of risk from single risk factors or in terms of multivariable risk scores. Novel risk markers, such as carotid intima-media thickness, high-sensitivity measurement of C-reactive protein, coronary artery calcium score, and genetic risk scores have been suggested as new ways to identify candidates for primary prevention of CVD through intensive risk-factor modification. Yet, many questions remain unanswered. Can these novel markers be used to identify adults who will benefit from statin therapy? How will novel markers affect medication adherence? Is screening using these markers cost-effective? Our opinion is that clinical trials of one or more of these novel tests, combined with monitoring of traditional risk factors, are needed in asymptomatic, low-risk populations.