Heart failure has been characterized by a reduction in cardiac contractile function resulting in reduced cardiac output. The clinical symptoms including mild tachycardia, reduced arterial pressure, increased venous or filling pressure and exercise intolerance have conceptually, to a large degree, been attributed to cardiac myocyte dysfunction. More recently, a vascular component has been recognized to contribute to heart failure. Among the most studied vascular mechanisms that might contribute to the development of heart failure has been the reduced production of nitric oxide or the reduced bioactivity of NO associated with both basic models of heart failure and disease in patients. The still evolving concept that heart failure is a cytokine activated state has, in addition, focused attention on the possibility that the cytokine driven isoform of NO synthase (NOS), iNOS, may produce sufficient quantities of NO to actually suppress cardiac myocyte function contributing to the reduced inotropic state in the failing heart. Thus, our view of the role of NO in the development of heart failure has evolved from simply a reduction in production of NO in blood vessels, to altered substrate availability (i.e. L-arginine), to increased scavenging of NO by superoxide anion, to increased production of NO from iNOS. As these concepts develop, our approach to the therapeutics of heart failure has also progressed with the recognition of the need to develop treatments directed towards addressing one or more of these etiologies. This review will focus on these aspects of the involvement of NO in the development of heart failure and some of the treatments that have developed from our understanding of the basic biology of NO to address these pathohysiologic states.