The 2013 American College of Cardiology Foundation/American Heart Association guidelines recommend combined isosorbide dinitrate (ISDN) and hydralazine to reduce mortality and morbidity for African-Americans with symptomatic heart failure (HF) and reduced ejection fraction, currently receiving optimal medical therapy (class I, level A). Nitrates can alleviate HF symptoms, but continuous use is limited by tolerance. Hydralazine may mitigate nitrate tolerance, and the ISDN-hydralazine combination in the Vasodilators in Heart Failure Trial (V-HeFT) I improved survival and exercise tolerance in men with dilated cardiomyopathy or HF with reduced ejection fraction, most notably in self-identified black participants. In the subsequent V-HeFT II, survival was greater with enalapril than with ISDN-hydralazine in the overall cohort, but mortality rate was similar in the enalapril and ISDN-hydralazine groups in the self-identified black patients. Consequently, in the African-American Heart Failure Trial (A-HeFT) in self-identified black patients with symptomatic HF, adding a fixed-dose combination ISDN-hydralazine to modern guideline-based care improved outcomes versus placebo, including all-cause mortality, and led to early trial termination. Hypertension underlies HF, especially in African-Americans; the A-HeFT and its substudies demonstrated not only improvements in echocardiographic parameters, morbidity, and mortality but also a decrease in hospitalizations, potentially affecting burgeoning HF health-care costs. Genetic characteristics may, therefore, determine response to ISDN-hydralazine, and the Genetic Risk Assessment in Heart Failure substudy demonstrated important hypothesis-generating pharmacogenetic data.