The article "Lack of Exercise is a Major Cause of Chronic Diseases" by Frank W. Booth, Christian K. Roberts, and Matthew J. Laye, published in *Comprehensive Physiology*, reviews the detrimental effects of physical inactivity on health and the prevention of chronic diseases. The authors argue that physical inactivity is a primary cause of most chronic diseases, including accelerated biological aging, low cardiorespiratory fitness, sarcopenia, metabolic syndrome, obesity, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, coronary heart disease, hypertension, stroke, cognitive dysfunction, depression, osteoporosis, and cancer. The article is structured into three main sections: conceptual information, primary literature supporting physical inactivity as a cause of chronic diseases, and additional considerations. The first third of the article provides foundational concepts, including definitions of physical activity, functional capacity, types of fitness, chronic diseases, and prevention. It also discusses historical evidence showing that physical inactivity reduces functional capacity and health, and highlights the distinction between cause and treatment. The mechanisms by which inactivity causes disease are different from those by which physical activity acts as a preventive measure, and gene-environment interactions play a significant role in the magnitude of these effects. The center portion of the article examines how physical inactivity initiates 35 separate pathological and clinical conditions, categorized under major health issues such as aging, metabolic disorders, cardiovascular diseases, cognitive functions, bone and connective tissue disorders, cancer, reproductive diseases, and digestive, pulmonary, and kidney diseases. The final portion of the article addresses clinical significance, the increasing risk factors in long-term sedentary individuals, the developmental and clinical consequences of inactive childhood and adolescence, and public policy. The authors emphasize that physical inactivity rapidly maladaptive the body, leading to substantial decreases in both total and quality years of life. They conclude that conclusive evidence exists that physical inactivity is a significant cause of chronic diseases and that physical activity primarily prevents or delays these diseases, suggesting that chronic disease need not be inevitable during life.The article "Lack of Exercise is a Major Cause of Chronic Diseases" by Frank W. Booth, Christian K. Roberts, and Matthew J. Laye, published in *Comprehensive Physiology*, reviews the detrimental effects of physical inactivity on health and the prevention of chronic diseases. The authors argue that physical inactivity is a primary cause of most chronic diseases, including accelerated biological aging, low cardiorespiratory fitness, sarcopenia, metabolic syndrome, obesity, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, coronary heart disease, hypertension, stroke, cognitive dysfunction, depression, osteoporosis, and cancer. The article is structured into three main sections: conceptual information, primary literature supporting physical inactivity as a cause of chronic diseases, and additional considerations. The first third of the article provides foundational concepts, including definitions of physical activity, functional capacity, types of fitness, chronic diseases, and prevention. It also discusses historical evidence showing that physical inactivity reduces functional capacity and health, and highlights the distinction between cause and treatment. The mechanisms by which inactivity causes disease are different from those by which physical activity acts as a preventive measure, and gene-environment interactions play a significant role in the magnitude of these effects. The center portion of the article examines how physical inactivity initiates 35 separate pathological and clinical conditions, categorized under major health issues such as aging, metabolic disorders, cardiovascular diseases, cognitive functions, bone and connective tissue disorders, cancer, reproductive diseases, and digestive, pulmonary, and kidney diseases. The final portion of the article addresses clinical significance, the increasing risk factors in long-term sedentary individuals, the developmental and clinical consequences of inactive childhood and adolescence, and public policy. The authors emphasize that physical inactivity rapidly maladaptive the body, leading to substantial decreases in both total and quality years of life. They conclude that conclusive evidence exists that physical inactivity is a significant cause of chronic diseases and that physical activity primarily prevents or delays these diseases, suggesting that chronic disease need not be inevitable during life.