Left ventricular dyssynchrony due to conduction system disease creates cardiac inefficiency even in normal hearts. Dyssynchrony in the failing heart results in the development of a discrete heart failure phenotype as it induces chamber heterogeneity at the cellular and molecular levels that leads to impaired excitation-contraction coupling, increased arrhythmia susceptibility, and decreased myocyte survival among other pathologic changes. Recent research has demonstrated that these biomolecular changes are amazingly reversed with cardiac resynchronization therapy, providing insight into how to target the therapy.