This thesis offers a comprehensive analysis of heart failure (HF) pharmacotherapy, emphasizing the transformative role of angiotensin receptor–neprilysin inhibitors (ARNIs), particularly sacubitril/valsartan, in managing heart failure with reduced ejection fraction (HFrEF). It effectively traces the historical evolution from symptomatic treatments to mechanism-based strategies targeting neurohormonal dysregulation. Central to the discussion is the “Fantastic Four” drug regimen—ARNIs, β-blockers, MRAs, and SGLT2 inhibitors—whose synergistic use has been shown to significantly improve mortality and morbidity. The thesis integrates mechanistic insights with evidence from landmark trials such as PARADIGM-HF and PIONEER-HF, demonstrating both efficacy and safety of ARNI therapy. It also explores the expanding potential of these therapies in HFpEF and pediatric populations. Overall, this work presents a well-structured and evidence-based perspective on modern HF treatment, underscoring the clinical impact of ARNI-based strategies.