Experimental and clinical evidence indicating an antiarrhythmic effect of cardiac sympathetic denervation has been available for 100 years. Experimental data show that left cardiac sympathetic denervation (LCSD), in particular, is not only antiarrhythmic, but also antifibrillatory—an effect exquisitely important for any clinical condition associated with a high risk of ventricular fibrillation and sudden cardiac death. LCSD has additional effects on both the coronary circulation and the mechanical performance of the left ventricle, with important implications for patients with ischaemic cardiomyopathy. Evidence also shows that LCSD increases the vagal activity directed to the heart, which has potential implications for the management of heart failure. In this Review, the current and novel clinical indications for LCSD are discussed, particularly in the context of results obtained in patients with channelopathies, such as long QT syndrome and catecholaminergic polymorphic ventricular tachycardia.