Stress has not always been accepted as a legitimate medical condition. The biomedical concept stress grew from tangled roots of varied psychosomatic theories of health that examined (a) the relationship between the mind and the body, (b) the relationship between an individual and his or her environment, (c) the capacity for human adaptation, and (d) biochemical mechanisms of self-preservation, and how these functions are altered during acute shock or chronic exposure to harmful agents. From disparate 19th-century origins in the fields of neurology, psychiatry, and evolutionary biology, a biological disease model of stress was originally conceived in the mid-1930s by Canadian endocrinologist Hans Selye, who correlated adrenocortical functions with the regulation of chronic disease. At the same time, the mid-20th-century epidemiological transition signaled the emergence of a pluricausal perspective of degenerative, chronic diseases such as cancer, heart disease, and arthritis that were not produced not by a specific etiological agent, but by a complex combination of multiple factors which contributed to a process of maladaptation that occurred over time due to the conditioning influence of multiple risk factors. The mass awareness of the therapeutic impact of adrenocortical hormones in the treatment of these prevalent diseases offered greater cultural currency to the biological disease model of stress. By the end of the Second World War, military neuropsychiatric research on combat fatigue promoted cultural acceptance of a dynamic and universal concept of mental illness that normalized the phenomenon of mental stress. This cultural shift encouraged the medicalization of anxiety which stimulated the emergence of a market for anxiolytic drugs in the 1950s and helped to link psychological and physiological health. By the 1960s, a growing psychosomatic paradigm of stress focused on behavioral interventions and encouraged the belief that individuals could control their own health through responsible decision-making. The implication that mental power can affect one’s physical health reinforced the psycho-socio-biological ambiguity that has been an enduring legacy of stress ever since. This article examines the medicalization of stress—that is, the historical process by which stress became medically defined. It spans from the mid-19th century to the mid-20th century, focusing on these nine distinct phases: 1. 19th-century psychosomatic antecedent disease concepts 2. The emergence of shell-shock as a medical diagnosis during World War I 3. Hans Selye’s theorization of the General Adapation Syndrome in the 1930s 4. neuropsychiatric research on combat stress during World War II 5. contemporaneous military research on stress hormones during World War II 6. the emergence of a risk factor model of disease in the post-World War II era 7. the development of a professional cadre of stress researchers in the 1940s and 50s 8. the medicalization of anxiety in the early post–World War II era 9. The popularization of stress in the 1950s and pharmaceutical treatments for stress, marked by the cultural assimilation of paradigmatic stress behaviors and deterrence strategies, as well pharmaceutical treatments for stress.