Underlying and precipitating causes of heart failure (HF) with reduced left ventricular ejection fraction (HFrEF) should be identified and treated when possible. Hypertension should be treated with diuretics, angiotensin-converting enzyme (ACE) inhibitors, and β-blockers. Diuretics are the first-line drugs in the treatment of patients with HFrEF and volume overload. Angiotensin-converting enzyme inhibitors and β-blockers (carvedilol, sustained-release metoprolol succinate, or bisoprolol) should be used in treatment of HFrEF. Use an angiotensin II receptor blocker (ARB) (candesartan or valsartan) if intolerant to ACE inhibitors because of cough or angioneurotic edema. Sacubitril/valsartan may be used instead of an ACE inhibitor or ARB in patients with chronic symptomatic HFrEF class II or III to further reduce morbidity and mortality. Add an aldosterone antagonist (spironolactone or eplerenone) in selected patients with class II–IV HF who can be carefully monitored for renal function and potassium concentration. (Serum creatinine should be ≤ 2.5 mg/dl in men and ≤ 2.0 mg/dl in women. Serum potassium should be < 5.0 mEq/l). Add isosorbide dinitrate plus hydralazine in patients self-described as African Americans with class II–IV HF being treated with diuretics, ACE inhibitors, and β-blockers. Ivabradine can be used in selected patients with HFrEF.