One of the defining features of heart failure (HF) is neurohormonal activation. The renin-angiotensin-aldosterone-system (RAAS) and sympathetic nervous system (SNS) cause vasoconstriction and fluid retention and, in response, the secretion of natriuretic peptides (NPs) from volume and pressure-overloaded myocardium promotes vasodilation and diuresis. Inhibition of the RAAS with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) has been the cornerstone of medical treatment for HF with a reduced ejection fraction (HFrEF) but, until recently, it was unclear how the beneficial effects of NPs may be augmented in patients with HF. Neprilysin, a metalloproteinase widely distributed throughout the body, plays a role in degrading the gross excess of circulating NPs in patients with HF. Early studies of neprilysin inhibition suggested possible physiological benefits. In 2014, the PARADIGM-HF trial found that sacubitril-valsartan, a combination of the ARB valsartan, and the neprilysin inhibitor sacubitril, was superior to enalapril in patients with HFrEF, reducing the relative risk of cardiovascular (CV) death or first hospitalisation with HF by 20%. Almost half of the patients with HF symptoms have a “preserved” ejection fraction (HFpEF); however, the PARAGON-HF study found that sacubitril-valsartan in patients with LVEF ≥45% had no effect on CV death or first and recurrent hospitalisations with HF compared to valsartan. Guidelines across the world have changed to include sacubitril-valsartan for patients with HFrEF yet, nearly 6 years after PARADIGM-HF, there is still uncertainty as to when and in whom sacubitril-valsartan should be started. Furthermore, there may yet be subsets of patients with HFpEF who might benefit from treatment with sacubitril-valsartan. This review will describe the mechanisms behind the outcome benefit of sacubitril-valsartan in patients with HFrEF and to consider its future role in the management of patients with HF.