Despite the benefit of cardiac resynchronization therapy (CRT) in patients with heart failure and conduction delay, a considerable number of patients do not respond substantially. Left ventricular lead position is an important factor in response, restricted by the patient's specific anatomy and local pathophysiology. Quadripolar leads could enhance response to CRT, offering 4 pacing locations along the distal end of the lead. Several quadripolar leads are available, all with different shapes and electrode spacing. Electrodes can be positioned in an ideal pacing location, determined by delayed mechanical or electrical activation, and away from phrenic nerve stimulation, high pacing thresholds, and fibrosis. Implantation is safe, with comparable or even lower complication rates compared with standard bipolar leads. Studies on biventricular pacing with quadripolar leads show apparent variations in acute hemodynamic response between pacing configurations, implying a patient-specific response. Pacing with an optimal pacing vector of a quadripolar lead benefits acute hemodynamic response. Multipoint pacing, pacing the left ventricle with 2 of 4 electrodes, could further enhance response. However, larger trials are needed to confirm these results, and results on long-term outcome of CRT with quadripolar leads and the benefit of multipoint pacing are warranted. We conclude that quadripolar leads are an important improvement in the treatment of heart failure patients with CRT.