The high rate of nonresponse to cardiac resynchronization therapy (CRT) has remained nearly unchanged since the treatment was introduced. We believe that this is directly related to the many persisting unknowns regarding the mechanical function of asynchronous hearts and the use of electrical stimulation to counteract the deleterious effects of that asynchrony. As a consequence, the key questions pertaining to the pre-implant, intra-implant, and postimplant phases remain unanswered or only partially answered. QRS duration is an imperfect selection criterion, as it does not discriminate the activation pattern. The inclusion of QRS morphology in the international professional practice guidelines is an important first step toward increasing the yield of this therapy. The invasive and the noninvasive electrical mapping techniques seem highly promising and need to be tested in large trials. The site of stimulation is a key element of the response to CRT; additional research must be pursued in this field.