Heart failure (HF) is a multi-faceted clinical condition affecting up to 2% of the population in the developed world and is linked to significant morbidity and mortality, therefore posing a major public health concern. To this date, pharmacotherapy for HF has mainly focused on chronic HF with reduced ejection fraction (HFrEF), with angiotensin converting enzyme inhibitors (ACEi) being at the centre of the management plan, alongside angiotensin-receptor-blockers (ARBs), β-blockers (BB) and mineralocorticoid receptor antagonists (MRAs). A novel and recently approved therapy, however, involving angiotensin receptor-neprilysin inhibitors (ARNI), has shown very promising results and comparable to those of ACEi, which raises the question of whether ACEi should remain the first-line treatment option for HFrEF. In this review, the evidence regarding the clinical efficacy of ACEi and ARNI in the treatment of HFrEF is discussed, with emphasis placed on the major landmark trials.