Strategies to support oxygenation can cause substantial harm through lung stretch injury, oxygen toxicity, transfusion risks and cardiac over-stimulation. Traditional goals of maintaining near normal cardiorespiratory parameters are most likely overly simplistic and are insensitive and nonspecific for tissue hypoxic effects. In order to reduce iatrogenic harm, it is conceivable that clinicians could be comfortable with lower levels of arterial oxygen content (eg, oxyhemoglobin values of < 88%: so called "permissive hypoxemia"), provided that there are ways to effectively monitor tissue hypoxia. We can learn more about hypoxic compensatory mechanisms from the fetus and from high altitude residents. We also need to learn better ways of monitoring tissue oxygenation, especially in "mission critical" tissues. Ultimately clinical trials will be needed to determine appropriate oxygenation targets to allow permissive hypoxemia.