Oxygen is both lifesaving and toxic. Appropriate use of oxygen aims to provide a balance between the two effects. Although local oxygen toxicity to the lung is well accepted, recent evidence has called into question the negative consequences of hyperoxemia in other organ beds. Hyperoxia following cardiac arrest, traumatic brain injury, and stroke has been shown to worsen outcomes. The role of hyperoxemia in mechanically ventilated patients, in the face of non-toxic inspired oxygen concentrations, is less clear. This paper will review the data for and against the use of conservative oxygen targets and the avoidance of hyperoxemia in mechanically ventilated patients. Key words: hyperoxia; hyperoxic acute lung injury; lung protective ventilation; oxygen toxicity; reactive oxygen species; ventilator-induced lung injury. [Respir Care 2016;61(6):801-817.