Conventionally, a substantial number of patients with acute respiratory failure require mechanical ventilation (MV) to avert catastrophe of hypoxemia and hypercapnia. However, mechanical ventilation per se can cause lung injury, accelerating the disease progression. Extracorporeal membrane oxygenation (ECMO) provides an alternative to rescue patients with severe respiratory failure that conventional mechanical ventilation fails to maintain adequate gas exchange. The physiology behind ECMO and its interaction with MV were reviewed. Next, we discussed the timing of ECMO initiation based on the risks and benefits of ECMO. During the running of ECMO, the protective ventilation strategy can be employed without worrying about catastrophic hypoxemia and carbon dioxide retention. There is a large body of evidence showing that protective ventilation with low tidal volume, high positive end-expiratory pressure, and prone positioning can provide benefits on mortality outcome. More recently, there is an increasing popularity on the use of awake and spontaneous breathing for patients undergoing ECMO, which is thought to be beneficial in terms of rehabilitation.