Heart failure with reduced ejection fraction (HFrEF) represents a significant global health burden, affecting more than 60 million individuals worldwide and contributing substantially to morbidity, hospitalization, and pre-mature mortality. Despite advances in evidence-based therapies, managing HFrEF remains complex. Contemporary treatment strategies are anchored in four foundational drug classes – angiotensin-converting enzyme inhibitors or angiotensin receptor blockers or angiotensin receptor-neprilysin inhibitors; beta-blockers; mineralocorticoid receptor antagonists; and sodium-glucose cotransporter-2 inhibitors. These “four pillars” of HFrEF treatment have proven benefits in improving survival and quality of life. However, effective treatment involves not only prescribing these medications, but also timely initiation, thoughtful combination, and careful uptitration to target doses shown to be effective in clinical trials. Real-world data reveal that many patients do not receive these therapies optimally, often due to inappropriate doses or delays in initiation, which limits their clinical benefits. Early initiation of all four drug classes – ideally within 30 days of diagnosis or a decompensated event – can significantly reduce hospitalizations, disease progression, and all-cause mortality. In selected patients, additional treatments, such as vericiguat, ivabradine, and iron supplementation may provide further benefit, particularly for those with persistent symptoms or iron deficiency. Thus, managing HFrEF requires a comprehensive, individualized approach that aligns clinical practice with evidence-based protocols to maximize outcomes and reduce the health burden of patients.