HFrEF is a progressive and complex condition with very high rates of mortality and hospitalizations. Recently, positive cardiovascular (CV) outcomes and reduced hospitalization for heart failure (HF) were noted in patients with HF with reduced ejection fraction (HFrEF) treated with novel emerging agents. The inclusion of the soluble guanylate cyclase (sGC) stimulator, vericiguat; and the sodium-glucose cotransporter-2 (SGLT2), empagliflozin and dapagliflozin; have revolutionized the treatment of patients with HFrEF. The treatment of HFrEF requires one or more drugs from several classes, as recommended in the guidelines. Many factors need to be considered when selecting therapy for these patients, including how to initiate, add, or switch therapies, and how to assess the effectiveness of these treatments using imaging and biomarkers. Recent additions to guidelines including SGLT2 inhibitors and vericiguat have the potential to significantly decrease risk for hospitalization for patients with HFrEF. Timely implementation of these therapies is critical to achieve the anticipated health benefits.