Epinephrine increases coronary and cerebral blood flow during cardiopulmonary resuscitation (CPR) through α-adrenergic mechanisms. Although experimental studies and preliminary clinical observations suggested that standard doses of epinephrine are too low, several major clinical trials failed to demonstrate significant improvement with high-dose therapy. The limited effectiveness of epinephrine in any dose may be in part due to the adverse effects of β-adrenergic stimulation on myocardial oxygen requirements during ventricular fibrillation. However, there is no convincing evidence that vasoconstricting agents lacking β-adrenergic effects are more efficacious. Because the intense sympathetic neurohumoral stimulation of the heart that accompanies cardiac arrest results in high myocardial oxygen requirements, it is unlikely that any pharmacologic intervention will be able to prevent myocardial ischemia during CPR unless myocardial oxygen requirements are reduced. Moreover, the potential efficacy of pharmacologic interventions during CPR is limited by the overwhelming influences of underlying disease processes and the duration of antecedent circulatory arrest on resuscitation outcomes.