Mechanical ventilation is necessary for treating patients with severe brain injury because it guarantees the airway (through endotracheal intubation), permits sedation (and even curarization), and prevents hypoxemia and/or hypercapnia. Hyperventilation continues to be a focus of debate in the current literature. Nevertheless, the weight of scientific evidence to date suggests that it should not be applied prophylactically during the first 24 hours and that patients should not be hyperventilated for prolonged periods in the absence of intracranial hypertension. Acute lung injury and respiratory distress are among the most frequent and serious complications related to severe brain injury that benefit from the use of positive end-expiratory pressure (PEEP) and ventilation to protect the lung. Gas insufflation through the trachea is a promising therapeutic option for correcting hypercapnia secondary to ventilation for lung protection in such patients. Finally, multimodal monitoring (intracranial pressure, central venous pressure, oxygen saturation detected in the jugular bulb, cerebral oxygen pressure) is recommended for adjusting PEEP and controlling hyperventilation.