Angiotensin-converting enzyme inhibitors (ACE-Is) and beta-adrenergic receptor blockers (BBs) have been effective in reducing cardiovascular morbidity and mortality in patients with heart failure (HF) and left ventricular systolic dysfunction (LVSD). Angiotensin receptor blockers and aldosterone blockers have also been shown to be effective. Although ACE-Is and BBs remain the therapies of choice for patients with HF-LVSD, many clinicians have attempted to further reduce patient morbidity and mortality by adding another inhibitor or blocker of the renin-angiotensin-aldosterone system to an ACE-I or BB. This article reviews the efficacy and safety of adding another renin-angiotensin-aldosterone system inhibitor or blocker to an ACE-I or an angiotensin receptor blocker plus a BB in patients with HF-LVSD.