Acute respiratory distress syndrome (ARDS) is characterized by severe inflammatory response and hypoxemia. The use of mechanical ventilation (MV) for correction of gas exchange can cause worsening of this inflammatory response, called “ventilator-induced lung injury” (VILI). The process of withdrawing mechanical ventilation, referred to as weaning from MV, may cause worsening of lung injury by spontaneous ventilation. Currently, there are few specific studies in patients with ARDS. Herein, we reviewed the main aspects of spontaneous ventilation and also discussed potential methods to predict the failure of weaning in this patient category. We also reviewed new treatments (modes of mechanical ventilation, neuromuscular blocker use, and extracorporeal membrane oxygenation) that could be considered in weaning ARDS patients from MV.