Abstract: The role of endothelial dysfunction in the pathophysiology of heart failure is not yet clear. Endothelial dysfunction, induced by oxidative stress, contributes to the development of heart failure. Alterations of endothelial function and nitric oxide-cyclicguanosine monophosphate (NO-cGMP) pathway are involved in the pathophysiology of heart failure with both reduced and preserved ejection fraction. Indeed, an altered endothelium dependent vasodilatation, causing repeated episodes of ischemia/reperfusion, can induce a chronic stunned myocardium with systolic dysfunction and an increased diastolic stiffness with diastolic dysfunction. Moreover, the altered NO-cGMP pathway directly affects myocardial homeostasis. Endothelial dysfunction is associated with worse prognosis and higher rate of cardiovascular events. Potential therapeutic strategies targeting the NO-cGMP pathway in patients with heart failure will be discussed in this article. Although clinical data are still inconclusive, the NO-cGMP pathway represents a promising target for therapy.