Regular exercise has been shown to have both immediate and long-lasting benefits on cardiometabolic health, making it a cornerstone in the management of diabetes and cardiovascular conditions. Exerkines, defined as humoral factors responsive to acute or chronic exercise, have emerged as key players in conferring these benefits. Over the past decades, hundreds of exerkines have been identified from various organs, including skeletal muscle, heart, liver, adipose tissue, brain, and gut. Several exerkines, such as FGF21, IL-6, and adiponectin, have been explored for therapeutic use as exercise mimetics in treating metabolic and cardiovascular diseases. Recent advances in metagenomics have also identified gut microbiota as an additional class of exerkines that influence the efficacy of exercise in diabetes prevention, cardiac protection, and exercise performance. Multiomics-based studies have demonstrated the feasibility of using baseline exerkin signatures to predict individual responses to exercise in terms of metabolic and cardiorespiratory health. This review explores the molecular pathways through which exerkine networks mediate cardiometabolic adaptations to exercise by fine-tuning inter-organ crosstalk and discusses the potential for translating exerkin-based discoveries into therapeutic applications and personalized medicine for cardiometabolic diseases.Regular exercise has been shown to have both immediate and long-lasting benefits on cardiometabolic health, making it a cornerstone in the management of diabetes and cardiovascular conditions. Exerkines, defined as humoral factors responsive to acute or chronic exercise, have emerged as key players in conferring these benefits. Over the past decades, hundreds of exerkines have been identified from various organs, including skeletal muscle, heart, liver, adipose tissue, brain, and gut. Several exerkines, such as FGF21, IL-6, and adiponectin, have been explored for therapeutic use as exercise mimetics in treating metabolic and cardiovascular diseases. Recent advances in metagenomics have also identified gut microbiota as an additional class of exerkines that influence the efficacy of exercise in diabetes prevention, cardiac protection, and exercise performance. Multiomics-based studies have demonstrated the feasibility of using baseline exerkin signatures to predict individual responses to exercise in terms of metabolic and cardiorespiratory health. This review explores the molecular pathways through which exerkine networks mediate cardiometabolic adaptations to exercise by fine-tuning inter-organ crosstalk and discusses the potential for translating exerkin-based discoveries into therapeutic applications and personalized medicine for cardiometabolic diseases.