While numerous pathophysiologic mechanisms may lead to the onset and progression of chronic systolic heart failure, a variety of electrophysiologic abnormalities seen in the setting of chronic left ventricular dysfunction may also contribute to the natural history of the disease. Atrial, atrial-ventricular, and inter- and intraventricular conduction disturbances may place the failing ventricle at a further mechanical disadvantage, thus contributing to the functional impairment and poor outcomes associated with chronic heart failure. In the early 1990s, attempts at treating patients with end-stage systolic heart failure using conventional pacing strategies met with equivocal results. However, this work did provide further insight into the electromechanical consequences of advanced heart failure and suggested that atrial-synchronized biventricular pacing, or cardiac resynchronization therapy, might provide better and more consistent symptomatic and hemodynamic improvement. Several landmark clinical trials have evaluated the safety and efficacy of cardiac resynchronization therapy in New York Heart Association (NYHA) class III and IV heart failure. These studies have consistently shown statistically significant improvements in quality of life, NYHA functional class ranking, exercise tolerance, and left ventricular reverse remodeling. Some studies have suggested reductions in morbidity and mortality. This latter observation has been confirmed by a recent large-scale outcomes study. Thus, cardiac resynchronization therapy should be routinely considered in eligible NYHA class III and IV heart failure patients with ventricular dyssynchrony.