<p>Heart failure (HF) represents a significant global health challenge, characterized by high morbidity and mortality rates, decreased quality of life and a significant financial and economic burden. The prevalence of HF continues to rise, driven by an ageing population and an increasing burden of comorbidities such as hypertension, diabetes and obesity. Understanding the complex pathophysiology and developing effective treatments are critical for improving patient outcomes, yet the range of effective, life-prolonging medication classes has remained mostly constant in the last few decades. The introduction of angiotensin receptor neprilysin inhibitors (ARNI) was a major breakthrough in HF management, for the first time targeting the natriuretic peptide system in addition to the renin–angiotensin–aldosterone pathway to potentiate the effects of older drug classes. ARNI shows superiority in clinical outcomes compared to previous guideline-directed therapies, especially in patients with reduced ejection fraction (EF). It has now been implemented into international guidelines, endorsing its use in patients with HF and reduced ejection fraction (HFrEF) and HF with mildly reduced ejection fraction (HFmrEF). This review summarises the mechanism of action of Sac/Val, presents key clinical trials in a range of patient populations and HF aetiologies and outlines gaps in knowledge and potential novel uses of Sac/Val.</p>