Since its launch in 1948, the Framingham Heart Study has proved critical to shaping and enhancing our understanding of the history and root causes of coronary heart disease (CHD). A modern prototype for population-based studies, the Framingham Heart Study garnered widespread recognition in its early years for identifying risk factors for CHD and stroke and formulating CHD risk scores. Although the study remains iconic for its robust design and successes in uncovering risk factors for CHD, it has undergone transformations during the past 2 decades. The 21st century ushered in a new era in “molecular epidemiology” centered on cutting-edge genetic and “-omics technologies.” Framingham Heart Study investigators embraced these opportunities by pioneering genome-wide association studies at the population level and examining CHD through the lens of genetic variation, gene expression, and microRNA signatures. The Framingham Heart Study continues to evolve as it seeks to pinpoint new causes of disease with the hope of advancing personalized approaches to the treatment and prevention of CHD.