Pharmacological therapy of cardiac arrhythmias continues to evolve, with an increasing shift from class I to class III compounds and β-blockers. This is engendered by increasing concern that class I antiarrhythmic drugs might adversely affect mortality in patients with significant structural heart disease. The focus now is on complex molecules such as amiodarone and sotalol, as well as D-sotalol and structurally diverse newer class III agents (such as dofetilide, MK-499, ibutilide, almokalant, and MS-551 among many others), which act only by increasing the time course of myocardial repolarization. In the development of newer drugs, the main endpoint in clinical trials is also beginning to shift to mortality from surrogate endpoints such as those determined by Holter monitoring and programmed electrical stimulation. The advent of implantable devices allows the performance of clinical trials with a mortality endpoint in patients with manifest ventricular tachycardia and fibrillation while providing an alternative mode of therapy for these arrhythmias. In the case of manifest ventricular tachycardia and fibrillation and aborted sudden death, adequately designed, controlled trials can now be undertaken by the use of implantable devices. In such trials, implantable cardioverter-defibrillators may serve in lieu of the placebo arm of a randomized trial. Trials involving a comparison of implantable cardioverter-defibrillators and best medical therapy (for the present, amiodarone and sotalol) are currently in progress. To what extent the newer class III agents will meet the requirements of an ideal antifibrillatory agent that reduces mortality in patients with structural heart disease remains a continuing investigative challenge.