Applying mechanical ventilation and selecting ventilatory strategies in patients with acute brain injuries, especially those with lung damage, is challenging. Static (positive-end-expiratory-pressure) and dynamic (intra-tidal) changes in ventilator pressure, via complex pathways, influence cerebral arterial inflow and cerebral venous pressure and thus, cerebral blood volume and intracranial pressure. In this process, the relationship between airway pressure and pleural and trans-alveolar pressures, heavily affected by elastance of chest wall and lung, respectively, plays a central role. This relationship determines the extent to which a static and dynamic increase in airway pressure affect the cardiac function and venous return curves, which govern the static and dynamic arterial and central venous pressures. The integrity of cerebral autoregulation determines whether static changes in arterial pressure alter cerebral arterial inflow. Conversely, dynamic changes in arterial pressure during the breath are followed by corresponding changes in cerebral arterial inflow, due to inability of autoregulation to control rapid arterial pressure fluctuations. The flow dynamics in the jugular veins and the relationship between intracranial and sagittal sinus pressures determine whether static and dynamic changes in central venous pressure alter cerebral venous pressure. Setting the ventilator and planning strategies should be individualized and guided by the complex, interactive effects among central nervous, respiratory and cardiovascular systems on cerebral blood volume and cerebral perfusion and intracranial pressures. Following a logical framework, the clinician may anticipate the likely effects of ventilator settings and strategies on cerebral hemodynamics, enabling a more individualized approach in setting the ventilator and planning ventilatory strategies.