Both adipose tissues and liver are important metabolic organs critical for whole-body energy homeostasis and cardiometabolic health. These two organs communicate with each other and also with other major organs by releasing adipokines and hepatokines respectively, which form a complex hormonal network for regulation of glucose and lipid metabolism, insulin sensitivity and vascular functions. In particular, recent data from both our laboratory and others have shown that the hepatokine FGF21 exerts its pleiotropic metabolic and vascular benefits in part by regulating production of several adipokines in adipose tissues, especially adiponectin. In animal models (mice and monkeys) and patients with obesity and diabetes, therapeutic intervention with FGF21 causes a significant elevation of circulating adiponectin, an adipokine with insulin-sensitizing and vascular protective properties. On the other hand, a number of adipokines can act in both autocrine and paracrine manners to regulate the production and sensitivity of FGF21. We have obtained both clinical and animal evidence demonstrating that FGF21 resistance in obese adipose tissues leads to aberrant production of adipokines, which in turn causes metabolic inflammation, insulin resistance and vascular dysfunction. Lifestyle interventions, such as exercise, exert its cardiometabolic benefits in part by restoring the crosstalk between major adipokines and hepatokines.