Sudden cardiac death remains a daunting medical challenge. Rescuers have minutes to defibrillate the heart and prevent ischemic injury to critical organs. Cardiopulmonary resuscitation can extend the window for successful therapy but not for long. Complicating this further is the fact that few new therapies have been proven to protect against the postresuscitation phase of cardiac arrest, when as many as 90% of patients die despite successful defibrillation. Oxidants (both reactive oxygen and nitrogen) likely play critical roles during cardiac arrest, affecting defibrillation success by affecting cardiac gap junctions and after successful defibrillation causing multiorgan damage via direct and programmed cell death. Preconditioning is an intrinsic adaptive response to stress that targets this sequence of events and is highly protective against ischemia/reperfusion injury in the heart, brain, and other critical organs. Thus, how oxidants are affected by preconditioning could provide new insights and therapies for improving both defibrillation success and oxidant-mediated postresuscitation injury of sudden cardiac death.