It is epidemiologically established that obesity is frequently associated with the metabolic syndrome and poses an increased risk for the development of type 2 diabetes mellitus and cardiovascular disease. The molecular links that connect the phenomenon of obesity, per se, with insulin resistance and cardiovascular disease are still not fully elucidated. It is increasingly apparent that fully functional adipose tissue can be cardioprotective by reducing lipotoxic effects in other peripheral tissues and by maintaining a healthy balance of critical adipokines, thereby allowing the heart to maintain its full metabolic flexibility. The present review highlights both basic and clinical findings that emphasize the complex interplay of adipose tissue physiology and adipokine-mediated effects on the heart exerted by either direct effects on cardiac myocytes or indirect actions via central mechanisms through sympathetic outflow to the heart.