High-frequency ventilation (HFV) has been advocated to reduce lung injury and chronic lung disease (CLD) in preterm infants. Several randomized controlled trials have compared HFV with conventional mechanical ventilation (CMV) in preterm and term infants. This review first discusses animal data pertinent to optimizing the application of HFV in preterm infants. Second, a meta-analysis of all randomized controlled trials using HFV as an early intervention is presented. Finally, rescue use of HFV in preterm and term infants with respiratory failure or air leak syndromes is summarized. Eleven trials of early intervention with HFV are included in the meta analysis. Overall, chronic lung disease at 36 weeks postmenstrual age was reduced in patients treated with HFV, but mortality was not changed. The decrease in CLD, however, is confounded, as it is only based on small trials, whereas no pulmonary benefit was found in the three largest trials. Furthermore, HFV appears to increase the incidence of severe intracranial hemorrhages and periventricular leukomalacia. Therefore, routine elective use of HFV cannot be recommended at the present time. Limited data on rescue use of HFV suggest some benefits over continued CMV.