Heart failure represents a complex of symptoms caused by heart disease. The understanding of the underlying pathophysiological changes due to myocardial damage are crucial for an optimal diagnostic evaluation and treatment. The use of vasodilators and ACE inhibitors has led us to realize that the modulation of the neurohumoral system plays an eminent role in the morbidity and for survival of heart failure patients; therefore, the goal must be to recognize as early as possible myocardial damage, preventing the devastating effects of neurohumoral activation. This paper illustrates this aspect and discusses the clinically available therapeutic approaches.