A decade of research has established the role of cardiac resynchronization therapy (CRT) in medically refractory, moderate to severe systolic heart failure (HF) with intraventricular conduction delay. CRT is an electrical therapy instituted to reestablish ventricular synchronization in order to improve cardiac function and favorably modulate the neurohormonal system. CRT confers a mortality benefit, improved HF hospitalizations, and functional outcome in this population, but not all patients consistently demonstrate a positive CRT response. The nonresponder rate varies from 20% to 40%, depending on the defined response criteria. Efforts to improve response to CRT have focused on a number of fronts. Methods to optimize the correction of electrical and mechanical dyssynchrony, which is the primary target of CRT, has been the focus of research, in addition to improving patient selection and optimizing post-implant care. However, a major issue in dealing with improving nonresponse rates has been finding an accurate and generally accepted definition of "response" itself. The availability of a standard consensus definition of CRT response would enable the estimation of nonresponder burden accurately and permit the development of strategies to improve CRT response. In this review, we define various aspects of "response" to CRT and outline variability in the definition criteria and the problems with its inconsistencies. We describe clinical, laboratory, and pacing predictors that influence CRT response and outcome and how to optimize response.