The Framingham Heart Study (FHS), initiated in 1948, is the longest running prospective cohort study in the USA. Through >65 years of discovery, the FHS has contributed to our understanding of obesity, type 2 diabetes mellitus and prediabetes mellitus, the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD), and to how these conditions relate to our overall and cardiovascular-related mortality. This Timeline gives an overview of the substantial role the FHS has played in advancing the understanding of obesity, diabetes mellitus and NAFLD, and considers the direction the FHS will take in the years to come.