Currently, many centers use venovenous extracorporeal membrane oxygenation (VV-ECMO) as an adjunctive means of gas exchange to mechanical ventilation (MV) in patients with severe ARDS and refractory hypoxemia. One of the most interesting and controversial issues in the management of these patients is how to set the ventilatory strategy. The support provided by VV-ECMO makes the balance between risks and benefits of MV remarkably different from the conventional setting, since the need for MV to facilitate oxygenation and carbon dioxide clearance is greatly reduced or abolished during VV-ECMO. Therefore, the risks of causing ventilator-induced lung injury are of foremost importance; however, the issue of the optimum ventilatory strategy during VV-ECMO has not received sufficient consideration. This paper will describe the diverse MV strategies applied during VV-ECMO in clinical practice and will highlight specific pathophysiological considerations that are crucial in the process of defining optimal ventilation settings in patients with ARDS supported with VV-ECMO.