Spiral wave breakup is a proposed mechanism underlying the transition from ventricular tachycardia to fibrillation. We examined the importance of the restitution of action potential duration (APD) and of conduction velocity (CV) to the stability of spiral wave reentry in a two-dimensional sheet of simulated cardiac tissue. The Luo-Rudy ventricular action potential model was modified to eliminate its restitution properties, which are caused by deactivation or recovery from inactivation of K⁺, Ca²⁺, and Na⁺ currents (I _K,I _Ca, andI _Na, respectively). In this model, we find that1) restitution ofI _Ca andI _Na are the main determinants of the steepness of APD restitution;2) for promoting spiral breakup, the range of diastolic intervals over which the APD restitution slope is steep is more important than the maximum steepness;3) CV restitution promotes spiral wave breakup independently of APD restitution; and4) “defibrillation” of multiple spiral wave reentry is most effectively achieved by combining an antifibrillatory intervention based on altering restitution with an antitachycardia intervention. These findings suggest a novel paradigm for developing effective antiarrhythmic drugs.