Insulin is a hormone that possesses several therapeutic properties, some of which are only partially known and not definitely appreciated. Insulin appears to be an attractive therapeutic tool in several cardiovascular diseases and particularly in chronic heart failure (CHF). Insulin, in fact, exerts a direct effect on biological properties of myocytes by increasing the transmembrane glucose transport through glucose-specific insulin-regulated receptors, whose gene expression is down-regulated since the initial stages of myocyte hypertrophy. In addition, a hormonal antiapoptotic molecular effect has also been reported. These effects explain, at least in part, the observed improvement in ejection fraction and cardiac output in CHF patients when given insulin. Vasodilation is the most remarkable peripheral effect of insulin that seems to be due to a direct activity on vascular smooth muscle cells and, more remarkably, on an increased release of endothelium-derived relaxing factors, such as nitric oxide and vasodilator prostaglandins. In accordance with most recent clinical observations, this endothelial modulatory activity is not limited to the systemic circulation but involves also the pulmonary one and the alveolar-capillary interface, resulting in a facilitation of the alveolar gas diffusion. Such an effect on alveolar gas diffusion appears to play a major role in CHF patients. The present review focuses on the pathophysiological mechanisms underlying the insulin benefits, and emphasizes the hormone therapeutic applicability in a CHF setting.