Exercise exerkines are humoral factors released by various organs in response to physical activity, mediating cardiometabolic benefits. These include myokines from skeletal muscle, hepatokines and adipokines from the liver and adipose tissue, and gut-derived exerkines. Exerkines such as IL-6, FGF21, adiponectin, and myonectin play key roles in improving glucose metabolism, insulin sensitivity, and cardiovascular health. Exercise-induced exerkines also influence gut microbiota, which further modulates metabolic and cardiovascular outcomes. Recent studies show that exerkine profiles can predict individual responses to exercise, enabling personalized interventions. Exerkine-based therapies, including pharmacological mimetics and exercise regimens, are being explored for treating cardiometabolic diseases. The gut microbiome is emerging as a critical player in exerkine signaling, with specific microbial species contributing to metabolic adaptations. Research highlights the importance of understanding exerkine pathways, their regulation, and interactions to develop effective therapeutic strategies. Future directions include elucidating the physiological roles of exerkines, assessing how gender, age, and exercise parameters influence exerkine production, and constructing comprehensive multiomics maps to link exerkine changes to clinical outcomes. These advancements aim to improve personalized exercise and pharmacological interventions for cardiometabolic diseases.Exercise exerkines are humoral factors released by various organs in response to physical activity, mediating cardiometabolic benefits. These include myokines from skeletal muscle, hepatokines and adipokines from the liver and adipose tissue, and gut-derived exerkines. Exerkines such as IL-6, FGF21, adiponectin, and myonectin play key roles in improving glucose metabolism, insulin sensitivity, and cardiovascular health. Exercise-induced exerkines also influence gut microbiota, which further modulates metabolic and cardiovascular outcomes. Recent studies show that exerkine profiles can predict individual responses to exercise, enabling personalized interventions. Exerkine-based therapies, including pharmacological mimetics and exercise regimens, are being explored for treating cardiometabolic diseases. The gut microbiome is emerging as a critical player in exerkine signaling, with specific microbial species contributing to metabolic adaptations. Research highlights the importance of understanding exerkine pathways, their regulation, and interactions to develop effective therapeutic strategies. Future directions include elucidating the physiological roles of exerkines, assessing how gender, age, and exercise parameters influence exerkine production, and constructing comprehensive multiomics maps to link exerkine changes to clinical outcomes. These advancements aim to improve personalized exercise and pharmacological interventions for cardiometabolic diseases.