Composite angiotensin receptor-neprilysin inhibition (ARNi) represents a novel pharmacologic strategy for treatment of heart failure with reduced ejection fraction (HFrEF). In the PARADIGM-HF (Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial of 8399 subjects with HFrEF, treatment with the ARNi LCZ696 (sacubitril/valsartan) was associated with statistically important reductions in cardiovascular death, all-cause mortality, and the composite of cardiovascular death or heart failure hospitalization in comparison with enalapril. These data have supported the US and European regulatory approval of sacubitril/valsartan and guideline-based recommendations for its use in the treatment of selected patients with HFrEF. In this review, we discuss the evidence supporting use of ARNi in preference to angiotensin-converting enzyme-inhibitors or angiotensin receptor blockers in patients with HFrEF and identify a strategy for selection of appropriate patients for transition to ARNi in clinical practice.