Cardiac resynchronization therapy (CRT) has an established role in the treatment of end-stage, drug-refractory heart failure patients. Large randomized controlled trials have demonstrated that CRT improves morbidity and mortality and, in current practice, there is a substantial number of patients treated with CRT for off-label indications. Nevertheless, a significant proportion of patients lack clinical and echocardiographic improvement or even deteriorate. Novel, sophisticated echocardiographic techniques seem promising in predicting response to CRT but need adequate training and refinements. In the meantime, a comprehensive, multiparametric echocardiographic approach is probably required for a better evaluation of mechanical dyssynchrony. Other non-invasive cardiac imaging modalities, including magnetic resonance and multislice computed tomography, are providing further insight into the pathophysiological mechanisms underlying CRT response. An integrated approach based on multimodality cardiac imaging may aid to optimize the selection of heart failure patients who are candidate to CRT.