Positive end-expiratory pressure (PEEP) is externally applied through the ventilator circuit during mechanical ventilation. In injured regions with airless alveoli capable of being opened (recruitable alveoli), PEEP may diminish ventilator-induced lung injury by decreasing cyclic collapse and reopening. Alveolar recruitment may improve ventilation-perfusion matching and reduce exposure to oxygen (a cellular toxin). In less injured or healthy lung regions, PEEP may cause overdistention injury. Balancing recruitment and overdistention effects of PEEP is an important clinical challenge. We know little about the interactions between PEEP and Fio2, between circulatory status and PEEP/Fio2 used to increase arterial oxygenation, and between PEEP and lung injury etiology. Thus, the best strategy for adjusting PEEP remains uncertain. Two strategies are common: (1) titration of PEEP based on static or dynamic respiratory system pressure-volume (PV) relationships and (2) pairing of PEEP and Fio2 into a PEEP/Fio2 table.