Cardiac resynchronization therapy (CRT) emerged 2 decades ago as a useful form of device therapy for heart failure associated with abnormal ventricular conduction, indicated by a wide QRS complex. In this Review, we present insights into how to achieve the greatest benefits with this pacemaker therapy. Outcomes from CRT can be improved by appropriate patient selection, careful positioning of right and left ventricular pacing electrodes, and optimal timing of electrode stimulation. Left bundle branch block (LBBB), which can be detected on an electrocardiogram, is the predominant substrate for CRT, and patients with this conduction abnormality yield the most benefit. However, other features, such as QRS morphology, mechanical dyssynchrony, myocardial scarring, and the aetiology of heart failure, might also determine the benefit of CRT. No single left ventricular pacing site suits all patients, but a late-activated site, during either the intrinsic LBBB rhythm or right ventricular pacing, should be selected. Positioning the lead inside a scarred region substantially impairs outcomes. Optimization of stimulation intervals improves cardiac pump function in the short term, but CRT procedures must become easier and more reliable, perhaps with the use of electrocardiographic measures, to improve long-term outcomes.