Context: Care of patients with heart failure has been revolutionized throughout the past decade. A paradigm shift in the strategy for treating heart failure caused by systolic dysfunction is in progress. Despite the initial perception about β-blockers' safety, they are now the most extensively studied class of agents in the treatment of heart failure and have emerged as an important intervention to improve the clinical outcomes of heart failure patients. Objective: To provide scientific rationale for the use of β-blockers for patients with heart failure. Data Sources: All English-language articles of large, randomized controlled clinical trials assessing the mortality benefits of β-blockers in patients with heart failure were identified to provide the scientific rationale for the use of β-blockers in heart failure. Basic science studies were reviewed to provide an overview of the potential physiologic role of β-blockers in heart failure. Finally, clinical guidelines for the treatment of patients with heart failure were assessed to determine current recommendations for the use of these agents. Study Selection and Data Extraction: Randomized controlled clinical trials of β-blockers that included more than 300 subjects and assessed mortality as a primary end point. Data Synthesis: Of the 4 β-blockers tested in large randomized controlled clinical trials of patients with heart failure, 3 are available in the United States, bisoprolol, carvedilol, and metoprolol; 2 of these, carvedilol and metoprolol, have Food and Drug Administration indications for the treatment of heart failure. Compared with placebo treatment, β-blocker use is associated with a consistent 30% reduction in mortality and a 40% reduction in hospitalizations in patients with class II and III III heart failure. Conclusions: Tested in more than 10 000 patients, β-blockers reduce morbidity and mortality in class II through IV heart failure. Along with angiotensin-converting enzyme inhibitors, digoxin, and diuretics, β-blockers have strengthened the armamentarium to improve clinical outcomes of heart failure patients. The science supporting β-blockers must be translated into practice safely and rationally if the agents are to achieve their full potential.