AbstractRegular exercise has both immediate and long-lasting benefits on cardiometabolic health, and has been recommended as a cornerstone of treatment in the management of diabetes and cardiovascular conditions. Exerkines, which are defined as humoral factors responsive to acute or chronic exercise, have emerged as important players conferring some of the multiple cardiometabolic benefits of exercise. Over the past decades, hundreds of exerkines released from skeletal muscle, heart, liver, adipose tissue, brain, and gut have been identified, and several exerkines (such as FGF21, IL-6, and adiponectin) have been exploited therapeutically as exercise mimetics for the treatment of various metabolic and cardiovascular diseases. Recent advances in metagenomics have led to the identification of gut microbiota, a so-called “hidden” metabolic organ, as an additional class of exerkines determining the efficacy of exercise in diabetes prevention, cardiac protection, and exercise performance. Furthermore, multiomics-based studies have shown the feasibility of using baseline exerkine signatures to predict individual responses to exercise with respect to metabolic and cardiorespiratory health. This review aims to explore the molecular pathways whereby exerkine networks mediate the cardiometabolic adaptations to exercise by fine-tuning inter-organ crosstalk, and discuss the roadmaps for translating exerkine-based discovery into the therapeutic application and personalized medicine in the management of the cardiometabolic disease.