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Background: Cardiac resynchronization therapy (CRT) has been well established in multiple large trials to improve symptoms, hospitalizations, reverse remodeling, and mortality in well-selected patients with heart failure when used in addition to optimal medical therapy. Updated consensus guidelines outline patients in whom such therapy is most likely to result in substantial benefit. However, pooled data have demonstrated that only approximately 70% of patients who qualify for CRT based on current indications actually respond favorably. In addition, current guidelines are based on outcomes from the carefully selected patients enrolled in clinical trials, and almost certainly fail to include all patients who might benefit from CRT. Findings: The identification of patients most likely to benefit from CRT requires consideration of factors beyond these standard criteria, QRS morphology with particular consideration in patients with left bundle-branch block pattern, extent of QRS prolongation, etiology of cardiomyopathy, rhythm, and whether the patient requires or will eventually need antibradycardia pacing. In addition, the baseline severity of functional impairment may influence the type of benefit to be expected from CRT; for example, New York Heart Association class I patients may derive long-term benefit in cardiac structure and function, but no benefit in symptoms or hospitalizations can be reasonably expected. In contrast, certain New York Heart Association class IV patients may be too sick to realize long-term mortality benefits from CRT, but improvements in hemodynamic profile and functional capacity may represent vital advances in this population. Conclusion: This review evaluates the evidence regarding the various factors that can predict positive or even detrimental responses to CRT, to help better determine who benefits most from this evolving therapy.