Cardiac resynchronization therapy (CRT) is an established therapy for patients with advanced heart failure, depressed left ventricular function, and wide QRS complex. However, about 30 to 45% of patients do not respond to CRT. Assuming that the main therapeutic action of CRT is the correction of dyssynchronous myocardial contraction, a plethora of echocardiographic dyssynchrony parameters have been proposed to improve the prediction of response to CRT. However, one multicenter study has recently questioned the utility of any of these indexes. This review delineates the various causes of non-response to CRT, explains the different levels and mechanisms of dyssynchrony and gives a critical overview of currently available echocardiographic techniques for assessment of dyssynchrony. Based upon a discussion of the evidence coming from randomized multicenter studies and against the background of national and international cardiac societies' guideline recommendations on CRT, a rational basis for the evaluation of patients for CRT is proposed.