Cardiac resynchronization therapy (CRT) has been shown to improve survival, morbidity, symptoms, quality of life and exercise capacity, and to promote a beneficial reverse remodeling of the left ventricle in patients with heart failure, dilated hypokinetic left ventricle and wide QRS. The totality of evidence supports the use of CRT also in patients with mild symptoms (NYHA class II). However, the wider diffusion of CRT is determining a growing clinical and economic impact on national health systems. In clinical practice, in spite of "all-or-none" response, variable degrees of therapy response are commonly observed, but several evidence gaps remain to be addressed. According to recent guidelines for CRT implantation, a multiparametric combination of predictive factors emerging from the analysis of clinical trials, observational studies and registries, represents a useful tool for patient selection.