Acute decompensated heart failure (ADHF) is a common cause of hospitalizations. Intravenous nitroglycerin is widely used in the treatment of this condition. The use of this drug is based on its nitric oxide-mediated vasodilatory effect, which can lead to beneficial hemodynamic effects as well as improvement of myocardial ischemia and reduction of mitral regurgitation. However, information regarding the use of nitroglycerin for ADHF is limited to mostly hemodynamic evaluations in small groups of patients without cardiovascular outcome data. A single randomized, placebo controlled study that evaluated commonly used doses of nitroglycerin in patients with ADHF was disappointing and failed to show a significant hemodynamic effect or improvement of symptoms compared with placebo. The potential benefit of nitroglycerin seems to be limited by a decreased vasodilatory response in patients with heart failure, which requires an active titration of the drug and the use of high doses (>120 microg/min). In addition, the initial beneficial hemodynamic effect achieved with the appropriate dose of nitroglycerin is associated with neurohumoral activation and limited by an early development of nitrate tolerance that leads to a marked attenuation of the initial effect. More information obtained in large-scale studies that are appropriately designed to evaluate the effect of variable doses of nitroglycerin on short- and long-term cardiovascular outcome, with and without interventions shown to prevent nitrate tolerance, is needed before intravenous nitroglycerin can be recommended as a standard therapy for ADHF.