This critical review illustrates the pathophysiological aspects and available scientific evidence about cardiac contractility modulation therapy. A useful algorithm dealing with the essential decisional knots to consider for device implantation in patients with heart failure in NYHA class >II and ejection fraction ≤45% is presented. The present review paves the way for the development of an Italian registry aiming at analyzing the characteristics of implanted patients based on a multiparametric approach, including cardiac biomarkers, to identify clinical profiles and predictors of response to therapy. The "Answers and Questions" section provides useful insights into pathophysiology, technical specifications, clinically relevant scenarios and future perspectives.