It is of interest that the drugs having the most significant impact on total and sudden death mortality are those without direct electrophysiologic actions on myocardial excitable tissue. This observation may provide insight into mechanisms responsible for ventricular tachyarrhythmias causing cardiac arrest. One way to think about ventricular fibrillation is that it is the final common pathway of an electrically unstable heart. After all, the heart can “die” in only three major ways: electromechanical dissociation, asystole and heart block, and ventricular fibrillation, with the latter most common. It is the “upstream” events provoking the electrical instability that these drugs probably act upon (i.e., ischemia, fibrosis). Although we unquestionably need to pursue investigations into the electrophysiology of these ventricular tachyarrhythmias, more studies need to investigate the drugs affecting upstream events, because these agents appear to yield the greatest dividends, at least for the present. This article reviews these drugs and how they may be effective. (J Cardiovasc Electrophysiol, Vol. 14, pp. S87‐S95, September 2003, Suppl.)