Abstract Background In the 1920s, heart disease (a noncommunicable disease), was the new leading cause of death in the USA. Simultaneously, experimental progress in the study of stress provided scientific justification for a new type of risk factor. The objective of the present work is to examine the history of heart disease as a public health problem and the contribution of advancements in scientific knowledge about stress in the 1930s-1960s supporting the hypothesis of stress as one cause of disease. Results In the process of studying heart disease risk factors in the 1950s, medical practitioners became responsible for the early detection of risk factors in order to "catch" chronic disease in its earliest stage. Coronary heart disease specifically was a disease of white, middle class, professional males, and "stress" was hypothesized as one reason why this population was particularly vulnerable. Walter Cannon and Hans Selye provided experimental evidence that stress might cause physical disease. In the 1930s, Cannon described how the body seeks to maintain homeostasis. When the body's systemic equilibrium is challenged by something dangerous in the environment or an insult directly to the body, the sympathetic nervous system (SNS) and adrenals are stimulated. In the 1940s and 1950s, Selye discovered that a universal triad of stress effects (hypertrophy of the adrenal glands, involution of the thymus and lymphoid tissue, and ulceration in the gastrointestinal tract) was seen repeatedly after any noxious or aversive event (i.e., noise, shock, etc.). The stress responses occurred in a certain pattern, known as the general adaptation syndrome or GAS. Autopsy from Selye's laboratory animals showed that, in addition to the general pathological effects of GAS, arteries were thickened and hardened, just as would be seen in human victims of heart and circulatory disorders. Conclusions Since then, large scale, prospective epidemiological studies, meta-analyses, and systematic reviews, as well as smaller scale basic science studies, have established the relationship between stress and heart disease development and progression. Most evidence centers on depression and the biobehavioral mechanisms underlying its contribution to heart disease. However, effective prevention/intervention strategies that improve stress and physical disease outcomes are still needed.