Numerous clinical trials have evaluated the safety and efficacy of cardiac resynchronization therapy in patients with moderate or severe heart failure and ventricular dyssynchrony. Initial studies were observational or mechanistic in design and enrolled small numbers of patients. These investigations provided proof of concept in support of resynchronization therapy by demonstrating acute and chronic improvements in hemodynamics, echocardiographic measures of cardiac performance, and functional status. Of these early studies, the InSync Trial stands out as particularly important in suggesting the long-term clinical benefits of cardiac resynchronization therapy in advanced heart failure. Later, a series of randomized, controlled trials was initiated to definitively evaluate the effects of cardiac resynchronization on patient status and clinical outcomes. These landmark investigations included the MUSTIC, MIRACLE, MIRACLE ICD, and CONTAK CD trials. These studies consistently demonstrated statistically significant improvements in quality of life, New York Heart Association (NYHA) functional class ranking, exercise tolerance, and left ventricular reverse remodeling. Some studies suggested reductions in morbidity and mortality. This latter observation was confirmed by a recent, large-scale morbidity and mortality trial of cardiac resynchronization therapy in heart failure. Given these findings, cardiac resynchronization therapy should be routinely considered in eligible NYHA Class III and IV heart failure patients with ventricular dyssynchrony.