Although cardiac resynchronization therapy is currently used for treatment of refractory heart failure in patients with low ejection fraction and cardiac dyssynchrony, there is a substantial number of non-responders. This indicates that, in addition to cardiac dyssynchrony, there are other factors affecting response to cardiac resynchronization therapy. Pre-implant identification of these factors appears of crucial importance in order to finalize the resynchronization treatment to those patients who have the highest probability of a positive response. In this review the main non-dyssynchrony determinants of response to cardiac resynchronization therapy are presented and discussed.