Progressive vascular and myocardial remodeling in heart failure is effectively slowed by therapy with neurohormonal antagonists, including angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, aldosterone antagonists, and adrenergic-receptor blockers. These therapies, along with the correction of hemodynamic abnormalities, have dramatically reduced morbidity and mortality in patients with heart failure. Endothelial dysfunction, increased oxidative stress, and decreased bioavailability of nitric oxide (NO) also occur in heart failure. Data suggest that endothelial dysfunction and reduced NO bioavailability may be more prevalent in populations who self-identify as African Americans. Thus, differences observed in the African American population with respect to prevalence of heart failure, etiology, outcomes, and response to medication may in part be explained by differences in the relative contributions of neurohormonal activation and diminished NO bioavailability to the progression of heart failure. The African American Heart Failure Trial (A-HeFT) was designed to assess the benefit of fixed-dose combination isosorbide dinitrate-hydralazine (ISDN-HYD) in an African American population with advanced heart failure. The A-HeFT enrolled 1,050 African American patients with New York Heart Association (NYHA) class III-IV heart failure with dilated ventricles and low ejection fractions. Patients were randomized to receive either a fixed-dose combination of ISDN-HYD or placebo added to standard neurohormonal blockade. The primary end point was a composite score in which mortality, hospitalization, and quality of life were weighted. On July 19, 2004, the independent Data Safety Monitoring Committee recommended early termination of the trial because of a significant mortality benefit in the cohort receiving fixed-dose ISDN-HYD. The A-HeFT confirms the benefit of fixed-dose ISDN-HYD, which may enhance NO bioavailability in African American patients with NYHA class III-IV heart failure and suggests that NO-enhancing therapy is an effective new treatment strategy for heart failure. In addition, the A-HeFT affirms the critical importance of the inclusion of population subgroups in clinical trials both as a way to probe for pathophysiologic mechanisms of disease and to devise optimal treatment strategies. The rich and unique A-HeFT database will provide new opportunities to understand the pathophysiology and management of heart failure.