Modern medical and technological advances provide highly effective management for the treatment of patients with heart failure with reduced ejection fraction (HFrEF). In this review, the authors propose a 2-step approach to treatment that is straightforward, practical, and thorough. For the patient whose life now includes HFrEF, the physician's first step is to ensure that the patient is taking the 3 key medications ([1]  renin-angiotensin inhibitors (angiotensin receptor/neprilysin inhibitors, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers), [2]  β-blockers, and [3]  mineralocorticoid receptor antagonists) recommended in guideline-directed doses to attain comprehensive receptor blockade. Significant coexisting medical issues are also characteristic in patients with HFrEF. Therefore, the physician's second step is to address the comorbidities of heart failure to fulfill comprehensive patient care. This review presents evidence to implement the management of HFrEF and heart failure comorbidities that will reduce cardiac mortality and hospitalization and to avoid treatments that are of no benefit or may cause harm.