Positive end-expiratory pressure (PEEP) has been used during mechanical ventilation since the first description of acute respiratory distress syndrome (ARDS). In the subsequent decades, many different strategies for optimally titrating PEEP have been proposed. Higher PEEP can improve arterial oxygenation, reduce tidal lung stress and strain, and promote more homogenous ventilation by preventing alveolar collapse at end expiration. However, PEEP may also cause circulatory depression and contribute to ventilator-induced lung injury through alveolar overdistention. The overall effect of PEEP is primarily related to the balance between the number of alveoli that are recruited to participate in ventilation and the amount of lung that is overdistended when PEEP is applied. Techniques to assess lung recruitment from PEEP may help to direct safer and more effective PEEP titration. Some PEEP titration strategies attempt to weigh beneficial effects on arterial oxygenation and on prevention of cyclic alveolar collapse with the harmful potential of overdistention. One method for PEEP titration is a PEEP/FiO2 table that prioritizes support for arterial oxygenation. Other methods set PEEP based on mechanical parameters, such as the plateau pressure, respiratory system compliance, or transpulmonary pressure. No single method of PEEP titration has been shown to improve clinical outcomes compared with other approaches of setting PEEP. Future trials should focus on identifying individuals who respond to higher PEEP with recruitment and on clinically important outcomes (e.g., mortality).