Mechanical ventilation (MV) is critical in the management of many patients with acute respiratory distress syndrome (ARDS). However, MV can also cause ventilator-induced lung injury (VILI). The selection of an appropriate Vt is an essential part of a lung-protective MV strategy. Since the publication of a large randomized clinical trial demonstrating the benefit of lower Vts, the use of Vts of 6 ml/kg predicted body weight (based on sex and height) has been recommended in clinical practice guidelines. However, the predicted body weight approach is imperfect in patients with ARDS because the amount of aerated lung varies considerably due to differences in inflammation, consolidation, flooding, and atelectasis. Better approaches to setting Vt may include limits on end-inspiratory transpulmonary pressure, lung strain, and driving pressure. The limits of lowering Vt have not yet been established, and some patients may benefit from Vts that are lower than those in current use. However, lowering Vts may result in respiratory acidosis. Tactics to reduce respiratory acidosis include reductions in ventilation circuit dead space, increases in respiratory rate, higher positive end-expiratory pressures in patients who recruit lung in response to positive end-expiratory pressure, recruitment maneuvers, and prone positioning. Mechanical adjuncts such as extracorporeal carbon dioxide removal may be useful to normalize pH and carbon dioxide levels, but further studies will be necessary to demonstrate benefit with this technology.