The article reviews the molecular insights into exercise therapy for disease prevention and treatment. Despite extensive evidence of the benefits of exercise, the underlying biological mechanisms are not fully understood. Exercise induces the release of signaling molecules called *exerkines*, which mediate inter-organ communication and tissue adaptation. These molecules, including peptides, proteins, tissue metabolites, lipids, and nucleic acids, play crucial roles in various physiological processes. The review highlights the molecular underpinnings of exerkine secretion, receptor-dependent and receptor-independent signaling cascades, and their clinical implications in disease prevention and treatment. Key aspects include the diversity of exerkines, their secretion mechanisms, distribution, and interaction with target cells. The article also discusses the potential therapeutic applications of exerkines, such as in disease prevention, targeted exercise therapy, and the development of exercise-inspired pharmaceuticals. Understanding these mechanisms is essential for harnessing the health benefits of exercise and improving targeted exercise programs.The article reviews the molecular insights into exercise therapy for disease prevention and treatment. Despite extensive evidence of the benefits of exercise, the underlying biological mechanisms are not fully understood. Exercise induces the release of signaling molecules called *exerkines*, which mediate inter-organ communication and tissue adaptation. These molecules, including peptides, proteins, tissue metabolites, lipids, and nucleic acids, play crucial roles in various physiological processes. The review highlights the molecular underpinnings of exerkine secretion, receptor-dependent and receptor-independent signaling cascades, and their clinical implications in disease prevention and treatment. Key aspects include the diversity of exerkines, their secretion mechanisms, distribution, and interaction with target cells. The article also discusses the potential therapeutic applications of exerkines, such as in disease prevention, targeted exercise therapy, and the development of exercise-inspired pharmaceuticals. Understanding these mechanisms is essential for harnessing the health benefits of exercise and improving targeted exercise programs.