Respiratory failure is a frequent disease process encountered in the emergency department. There is significant need for improvement in the care of patients on mechanical ventilation. If not contraindicated, lung-protective ventilation strategies should be used. It is important to consider pathophysiology (shunting, dead space ventilation, and low venous admixture) when formulating treatment strategies in patients who are difficult to oxygenate or ventilate or when Pao₂, Paco₂, and pH can only be maintained at unsafe ventilator settings.