After failure of external defibrillation, return of cardiac activity with spontaneous circulation is contingent on rapid and effective reversal of myocardial ischemia. Closed-chest cardiopulmonary resuscitation (CPR) evolved about 30 years ago and was almost universally implemented by both professional providers and lay bystanders because of its technical simplicity and noninvasiveness. However, there is growing concern since the limited hemodynamic efficacy of precordial compression accounts for a disappointingly low success rate; especially so if there is a delay of more than 3 minutes before resuscitation is started. There is also increasing concern with the lack of objective hemodynamic measurements currently available for the assessment and quantitation of the effectiveness of resuscitation efforts. Accordingly, the resuscitation procedure proceeds without confirmation that it increases systemic and myocardial blood flows to levels that would be likely to restore spontaneous circulation. Continuous monitoring of end-tidal carbon dioxide (PETCO2) now appears to be a practical measurement which provides a noninvasive quantitative indication of both systemic blood flow and coronary perfusion pressure. Consequently, PETCO2 predicts the likelihood of successful resuscitation and guides the operator who may modify the technique of precordial compression to improve systemic and myocardial perfusion. Among the large polypharmacy for cardiac resuscitation, only alpha-adrenergic agents (which increase coronary perfusion pressure) and especially epinephrine are of proven benefit. Neither buffer agents nor calcium salts appear to improve outcome except under unique conditions. To the contrary, there is increasing awareness of adverse effects of pharmacologic interventions such that they may hinder the return of viable myocardial and cerebral function. This has constrained the routine use of all drugs except for the use of alpha-adrenergic agonists. More invasive interventions by which blood flow is restored such as open-chest cardiac massage or extra-corporeal pump oxygenation (ECPO) are consistently more effective than conventional CPR. Experimentally, both methods promptly restore systemic and myocardial perfusion to viable levels and thereby increase the likelihood that spontaneous circulation is restored even after prolonged cardiac arrest or failure of conventional CPR.