Urocortins and the corticotropin releasing hormone have a long evolutionary history. In the nervous system the corticotropin releasing hormone is responsible of anxiogenic effects associated with stress, while urocortins are concerned with adaptive behavior. Urocortins are also expressed in the heart, where they may play an autocrine/paracrine role binding to corticotropin releasing hormone-R2 receptors. The expression of endogenous cardiac urocortin is increased by in vitro ischemia-reperfusion damage, and the addiction of exogenous urocortins is associated with reduction of myocardial cell death during ischemia-reperfusion damage in vitro, ex vivo and in vivo. In isolated perfused heart urocortin enhances cardiac contractility and decreases high energy phosphates reduction after ischemia-reperfusion damage. Urocortin is also associated with peripheral and coronary vasodilation and with positive inotropic effect. There are experimental data which suggest a beneficial effect of urocortins in subjects with heart failure and a possible beneficial role of urocortin in preventing the iatrogenic ischemia-reperfusion damage caused by cardioplegic arrest during cardiac surgery. These early observations suggest that assessment of the clinical use of urocortin in heart failure and for the prevention of ischemia-reperfusion damage in cardiac surgery should be actively pursued.