Pharmacologic modification of cellular calcium handling recently moved into focus as an alternative for prevention and treatment of ventricular tachyarrhythmias. Calcium overload and spontaneous calcium release from the sarcoplasmatic reticulum are regarded as possible initiations of early and delayed afterdepolarization thereby triggering ventricular arrhythmias. In chronic heart failure, calcium overload is more likely to occur compared with healthy hearts, which is one explantation for the increased vulnerability in this condition. L-type calcium channel, sodium–calcium-exchanger (NCX), and ryanodine receptor are crucial for calcium homeostasis and therefore represent potential targets for antiarrhythmic drug therapy. Experimental studies have proven beneficial effects for all these three mechanisms in prevention and suppression of tachyarrhythmias. However, clinical data is mainly available for the L-type calcium channel inhibitor verapamil. Therefore, it is still a long way to clinical employment of drugs modifying cellular calcium handling for antiarrhythmic therapy.