Purpose of review Recent advances in cardiopulmonary resuscitation have led to greater understanding of cardio-cerebral-pulmonary interactions during the process. The purpose of this discussion is to update the physiologic understanding of these interactions during cardiopulmonary resuscitation, review the detrimental and beneficial effects of ventilation, and identify implications for clinical practice. Recent findings There is an inversely proportional relationship between mean intrathoracic pressure, coronary perfusion pressure, and survival from cardiac arrest. Increased ventilation rates and increased ventilation duration impede venous blood return to the heart, decreasing hemodynamics and coronary perfusion pressure during cardiopulmonary resuscitation. It has also been shown that there is a direct and immediate transfer of the increase in intrathoracic pressure to the cranial cavity with each positive pressure ventilation, also reducing cerebral perfusion pressure. The reduced amount of blood flowing through the pulmonary bed during cardiopulmonary resuscitation tends to be overventilated, compromising hemodynamics to both, the heart and brain and resulting in ventilation/perfusion mismatch. Summary The fundamental hemodynamic principle of, intrathoracic pressure defines cardio-cerebral-pulmonary interactions during cardiopulmonary resuscitation. Further research is essential to optimize these interactions during treatment of profound shock.