Heart failure is one of the major causes of hospitalization in Italy and the Western world and is characterized by different pathophysiological conditions and multiple precipitating factors. The state of congestion, which is the main clinical presentation on admission, is treated in the majority of cases with diuretic therapy until hemodynamics are normalized and symptoms resolved. Treatment with loop diuretics, although widely used in the treatment of chronic heart failure, may result in diuretic resistance, electrolyte and volemic imbalance, neurohormonal activation, and worsening renal function. In this article the mechanisms of diuretic resistance and the strategies used to treat it and to optimize diuretic therapy of heart failure are discussed.