In the last years, the treatment of heart failure has radically changed, as has knowledge of this complex and heterogeneous clinical syndrome. This is largely due to the results of several multicenter clinical trials, which have been undertaken since the late 80's. These trials have not only contributed to the elaboration of present-day treatment protocols, but also to a better understanding of the pathophysiologic mechanisms involved in heart failure. In the past, heart failure was generally interpreted on the basis of pathophysiologic models according to which hemodynamic abnormalities played a very important role in determining the clinical presentation and evolution of the disease. This led to the use of digitalis, diuretics, inotropic drugs and vasodilators for the treatment of heart failure. More recently, improved knowledge of the pathophysiologic mechanisms involved in the progression of this disease has highlighted the central role and the complexity of various neurohormonal mechanisms. Antagonism of these systems has proved to be the only strategy which favorably modifies the natural history of heart failure. The proved effectiveness of ACE-inhibitors and particularly of beta-blockers in patients with heart failure and left ventricular systolic dysfunction was the most convincing demonstration of the validity of this model. However, the evolution and updating of the guidelines on the treatment of heart failure should only be considered as the first step in the development of strategies aimed at extending these principles to daily clinical practice and in particular to the real patient who is different from patients typically enrolled in heart failure trials. Moreover, the development of new effective models for the management of the ever-growing number of patients with heart failure is of utmost urgency.