Based on current knowledge of pulmonary mechanics and the results of clinical studies, we have reviewed principles that govern gas exchange during assisted ventilation in infants with RDS. Guidelines for changes in ventilator settings have been presented with respect to their specific effects on CO2 elimination and O2 uptake. In addition, their possible mechanisms of action and potential side effects have been addressed. General strategies have been presented, but they must be employed with caution. All infants will not exhibit the expected response to changes in ventilator setting, and thus their ventilatory management, as well as their general medical care, will need to be individualized.