Exercise has been recognized as an important non-pharmacological approach for the prevention, treatment, and rehabilitation of cardiovascular diseases, but the mechanisms of exercise in promoting cardiovascular health remain unclear. Exercise generates cardiac benefits via stimulating muscle to secret hundreds of myokines that directly enter circulation and target heart tissue. Therefore, inter-organ communication between skeletal muscle and heart may be one important regulating pattern, and such communication can occur through secretion of molecules, frequently known as myokines. Irisin, a newly identified myokine, is cleaved from fibronectin type III domain-containing protein 5 (FNDC5) and secreted by the stimulation of exercise. Recently, accumulating evidence focusing on the interaction between irisin and cardiac function has been reported. This review highlights the molecular signaling by which irisin regulates the benefits of exercise on cardiac function both in physiological and pathological process, and discusses the clinical potential of irisin in treating heart diseases. Exercise generates various cardiovascular benefits through stimulating skeletal muscle to secrete irisin. The exercise "hormone" irisin, both produced by exercise or recombinant form, exerts therapeutic effects in a group of cardiovascular disorders including heart failure, myocardial infarction, atherosclerosis and hypertension. However, the molecular mechanisms involved remain ambiguous.This review highlights the most up-to-date findings to bridge the gap between exercise, irisin and cardiovascular diseases, and discusses the potential clinical prospect of irisin.