This review attempts a catalogue raisonné of the treatment paradigms developed over the past 20 years that have substantially reduced the disability, morbidity, and mortality associated with the syndrome of chronic heart failure. Compensatory adjustments of the circulation to myocardial injury include an increase in hemodynamic resistance, but also, and importantly, the activation of neurohormonal systems, primarily the renin-angiotensin-aldosterone system (RAAS) and sympathetic adrenergic nervous system. Reduced stroke volume is offset by increased peripheral resistance and to some extent by an increase in heart rate. These compensatory mechanisms are now targeted by therapeutic intervention based on RAAS inhibition using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists, and on sympathetic inhibition using Βblockers, initiated by titration to minimize the risk of an introductory negative inotropic effect. Elevation of the resting heart rate above 70 bpm despite recommended therapy is a modifiable risk factor and an indication to add heart rate reduction as a treatment target above and beyond neurohormonal blockade. Direct sinus node inhibition using a pure heart rate–reducing agent is thus a promising new strategy in patients remaining symptomatic with an elevated heart rate, especially those whose comorbidity renders them intolerant of Βblockers.