© 2019 Elsevier Inc. All rights reserved. Despite more than a century of research, cardiovascular disease (CVD) and coronary heart disease (CHD) are the leading causes of death in the developing world. Since the early days of CVD research, the underlying cause and putative prevention strategies remain elusive. This chapter discusses the history of the lipid hypothesis, from the initial observations of Anitschkow and Chalatow to the industrious work of Gofman and the further studies of Ancel Keys, who endeavored to discover the role of cholesterol and saturated fat in CVD. The Seven Countries Study identified diet, saturated fat, and cholesterol as the underlying causes of CVD development. This chapter delivers an overview of the early research that formed the ¿lipid hypothesis,¿ which led to the development of modern treatment and prevention strategies for CVD.