Despite significant improvement in therapy and management, heart failure remains a worrisome disease state that is especially problematic in special populations. African Americans suffer a disproportionately higher prevalence of heart failure when compared to other populations. It has been recently demonstrated that vasodilator therapy using the combination of isosorbide dinitrate (ISDN) and hydralazine (HYD) as an adjunct to background evidence-based therapy appears to display the strongest signal of benefit in reducing mortality and morbidity in the African American population. Through review of the retrospective and more recent prospective data, we will focus on the benefit of ISDN-HYD as adjunctive therapy for use in African Americans with systolic heart failure on concomitant appropriate evidence based therapy. This review also closely examines some of the potential contributions to endothelial dysfunction in African Americans, and the relationship of vascular homeostasis and nitric oxide. The role of oxidative stress in left ventricular dysfunction will also be explored as a reduction of oxidative stress offers particular promise in the management of heart failure. Although neurohormonal blockade has been responsible for notable event reductions in patients with systolic heart failure, the addition of ISDN-HYD, vasodilator therapy that enhances nitric oxide and reduces oxidative stress, further improves quality of life and survival in African American patients with heart failure. These findings strongly imply that nitric oxide enhancement and/or oxidative stress reduction may be important new therapeutic directions in the management of heart failure.