Heart failure (HF) is a clinical syndrome due to structural and/or functional cardiac anomalies, accompanied by elevated natriuretic peptide levels and/or cardiogenic pulmonary or systemic congestion; severely compromising patients' health, performance and quality of life. The advancement of novel treatment and their endorsement by international medical and scientific societies have shifted the treatment of HF with reduced ejection fraction (HFrEF) towards quadruple therapy: an angiotensin receptor-neprilysin inhibitor or an angiotensin-converting enzyme inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist and a sodium/glucose co-transporter-2 inhibitor (SGLT2i). This paper reviews the available literature on state-of-the-art diagnostic and therapeutic advances in HFrEF, discusses landmark trials that shifted the paradigm towards quadruple therapy in HFrEF, visits the potential challenges in Lebanon and globally, proposes an algorithm for treatment introduction and sequencing in HFrEF and highlights clinical considerations for HFrEF management and patient education and follow-up. This practical guidance could serve cardiologists and other medical specialists in identifying clinical signs of HFrEF, diagnosing patients, referring them or prescribing the components of quadruple therapy, and offering medical advice and follow-up. We highlight the role of SGLT2is in HF management and their effectiveness in reducing rates of hospitalization for HF as well as cardiovascular deaths, with satisfactory safety profile.