Knowledge of the interrelation of the central nervous system-respiratory axis is crucial to the management of patients with head injuries with or without concomitant pulmonary-thoracic problems. Damage to the central nervous system (CNS) can result in unexplained hypoxemia, noncardiac pulmonary edema, altered patterns of respiration, and an increased risk of aspiration. The damaged thorax and lung can contribute to brain ischemia and rises in intracranial pressure. The treatment of one end of the CNS-respiratory axis is not without effect on the other end of the continuum. Corticosteroids, diuretics, mannitol, iatrogenic hyperventilation, barbiturates, and vasopressors are used in the management of patients with head trauma, but may have an impact on oxygenation and ventilation. When positive end expiratory pressure is used in the management of a pulmonary process, it should be optimized and used with caution while monitoring for its effect on intracranial pressure. Pulmonary toilet, while remaining a necessity, must be performed in a manner so as to minimize potential negative effects on the brain. Hyperoxia and hypothermia should be avoided. Mechanical ventilation should be used as dictated by the desired PaCO2 and not as a mandatory adjunct to endotracheal intubation.