Activation of the sympathetic nervous system (SNS) is a fundamental component of the pathophysiology of heart failure. Prolonged SNS activation contributes to several of the clinical sequelae of heart failure. Extensive clinical research has shown that inhibition of the SNS in patients with heart failure improves a variety of outcomes, including mortality, hospitalization for heart failure, progression of symptoms, and sudden cardiac death. The cornerstone therapy for inhibiting the SNS is administering drugs that antagonize the β-adrenergic receptor (β-blockers). A robust body of evidence shows that β-blockers reduce symptoms and improve outcomes in patients with heart failure and reduced ejection fraction. Non-pharmacologic therapies also have been found to improve outcomes in patients with heart failure via inhibition of the SNS. Here, we review the literature that supports these pharmacologic and non-pharmacologic therapies and offer practical advice regarding their application in clinical care.