With the dramatic rise in coronary heart disease (CHD) during the first half of the 20th century, the newly formed National Heart Institute realized the significant gap in knowledge about the causes of CHD and embarked in 1947 on planning what was to become the renowned Framingham Heart Study. Dr. Thomas Royal Dawber’s initial paper on the design of the project described studying up to 6,000 persons in a single geographic area and the formation of a technical advisory committee of 11 physicians in cardiology and public health to determine the hypotheses and protocol. A comprehensive physical examination and series of measurements and laboratory work were proposed and the initial examination was completed in 1952. The first paper describing 4 years of follow-up was published in 1957, and this was followed by a subsequent report in 1959 describing 6 years of follow-up. The first follow-up report described sex and age group differences in incidence of CHD and pointed out the noteworthy prominence of sudden cardiac death as the first manifestation of CHD and the initial observations regarding the significance of elevated blood pressure, cholesterol, and overweight in predicting future CHD. Importantly, the significance of a combination of risk factors for identifying those at highest risk was described as well as how the number of risk factors related to risk (the beginnings of what was decades later to become the famous risk scores from Framingham). Dr. William Kannel’s 1961 publication, “Factors of Risk in the Development of Coronary Heart Disease,” first highlighted the term risk factors, and it described how specific levels of cholesterol, blood pressure, as well as how electrocardiographic left ventricular hypertrophy predicted future CHD incidence. The standardized measurement of risk factors and follow-up in Framingham served as an important precedent for future observational studies designed and directed by what is now the National Heart, Lung, and Blood Institute, including the ARIC (Atherosclerosis Risk in Communities) study, the CARDIA (Coronary Artery Risk Development in Young Adults) study, the CHS (Cardiovascular Health Study), and the MESA (Multiethnic Study of Atherosclerosis). These studies and others continue the legacy that Framingham began more than 60 years ago into the investigation of the epidemiology of cardiovascular diseases.