The Framingham study provided critical and extremely valuable information regarding risk factors associated with the development of atherosclerotic cardiovascular disease (5- 7). The INTERHEART study demonstrated that nearly 90% to 95% of population-attributable risk of myocardial infarction is related to 9 potentially modifiable risk factors (smoking, apoprotein B/apoprotein A1 ratio, hypertension, diabetes, abdominal obesity, psychosocial factors, daily consumption of fruits and vegetables, regular alcohol intake, and regular physical activity) that apply to men and women, old and young, and in all regions of the world (8). Thus, risk factor inventory–based prediction models> using the FRS have been recommended as the cornerstone for risk stratification of asymptomatic subjects and matching intensity of preventive interventions (specifically, lipid-lowering drug therapy and cholesterol targets) to the magnitude of the predicted risk, as suggested by the National Cholesterol Education Program (NCEP) and the Adult Treatment Panel III (ATP III) (9- 10). Assessment of a few readily available clinical and laboratory variables such as age, sex, total cholesterol level, high-density lipoprotein cholesterol level, smoking status, and systolic blood pressure are used to calculate a 10-year risk of cardiovascular events. According to the NCEP/ATP III guidelines, subjects are considered to be at low risk if the estimated 10-year event rate is <10%, at high risk if the 10-year event rate is >20%, and at intermediate risk if the 10-year event rate is between 10% and 20%. Based on this scheme of risk stratification, NCEP guidelines suggest cholesterol goals for each of the subsets (9- 10). In 2003, the American College of Cardiology Bethesda Conference on Atherosclerosis Imaging suggested that low risk should be defined as a 10-year risk of ≤5% and intermediate risk defined as a 10-year risk of 6% to 20%. Although FRS and NCEP/ATP III guidelines are relatively simple, inexpensive, and useful, they are not good enough by themselves (11). Limitations of the FRS and NCEP/ATP III guidelines include a substantial underestimation of lifetime risk, especially in women when only a 10-year risk model is used, misclassification of high-risk subjects as low or intermediate risk, and misclassification of very low-risk subjects into higher strata of risk (11). Karim et al. (12) showed that in an ethnically diverse group of 498 asymptomatic men and women, 312 (63%) had a low FRS, and of these, 214 (69%) had noninvasive imaging evidence of subclinical atherosclerosis in ≥1 of the 3 vascular beds (coronary, aortic, and carotid). In the same study, of the 68 subjects with subclinical atherosclerosis in all 3 vascular beds, 35% had a low-risk FRS, 41% had an intermediate-risk FRS, and only 23% had a high-risk FRS (12). Furthermore, Akosah et al. (13) pointed out the shortcomings of the FRS in a study of 222 patients (men younger than 55 and women younger than 65 years of age) presenting with their first acute myocardial infarction over a 3-year period who were asymptomatic before the acute event. Based on their FRS, 75% of these patients would have been considered ineligible for statin use under the current NCEP guidelines that match intensity of treatment to the baseline FRS (13). A minority of patients with coronary heart disease have none of the traditional risk factors, but, more importantly, in a large proportion of patients with ≥1 risk factors, coronary heart disease does not develop (14). Furthermore, there is considerable variation in the severity of atherosclerotic burden at any given level of risk factor exposure, presumably attributable to additional known or unknown genetic and environmental risk factors and risk modifiers. The FRS also places a substantial number of women in the low-risk category using 10-year risk estimates even though they have a high lifetime risk; thus, very few women will reach the threshold for initiation of lipid-lowering or aspirin therapy (11,15). The FRS does not incorporate family history and many of the components of metabolic syndrome, both of which are important risk factors for coronary heart disease. A substantial number (>60% to 70%) of unheralded cardiovascular events occur in “low” and “intermediate” risk categories (16). Nasir et al. (17) showed that 79% of young men and women with significant coronary atherosclerotic burden displayed by coronary calcification were not eligible for pharmacotherapy based on current NCEP-ATP III guidelines. Although groups of patients can be placed in risk categories, many patients at risk would not be recommended for lipid-modifying therapy, and many patients in whom an event will not develop would be needlessly targeted for aggressive medical management (11). Thus, FRS and NCEP/ATP III guidelines, although reasonable for populations, remain suboptimal for individual subjects. In 2007, Ridker et al. (18) introduced the Reynolds Risk Score (RRS) for risk assessment in women, which, in addition to traditional risk factors, also incorporated high-sensitivity C-reactive protein (hsCRP) and family history of premature coronary artery disease. The RRS reclassified 30% of women estimated to be in the intermediate-risk group by the traditional FRS into a higher or lower risk category with improved accuracy. Subsequently, the RRS was tested in 10,724 initially healthy nondiabetic men age 50 years or older from the Physicians Heath Study who were followed for 10.8 years (19). The RRS was shown to be superior to the traditional FRS in predicting risk. Despite improved risk assessment with RRS compared with the traditional FRS, neither scheme is sufficiently accurate for individual risk assessment and, unlike the FRS, the RRS has not yet been fully validated outside the Women's Health Study and Physicians Health Study participants.