AbstractHigh-frequency ventilation (HFV) has been used as a respiratory support mode for neonates for over 30 years. HFV is characterized by delivering tidal volumes close to or less than the anatomical dead space. Both animal and clinical studies have shown that HFV can effectively restore lung function, and potentially limit ventilator-induced lung injury, which is considered an important risk factor for developing bronchopulmonary dysplasia (BPD). Knowledge of how HFV works, how it influences cardiorespiratory physiology, and how to apply it in daily clinical practice has proven to be essential for its optimal and safe use. We will present important aspects of gas exchange, lung-protective concepts, clinical use, and possible adverse effects of HFV. We also discuss the study results on the use of HFV in respiratory distress syndrome in preterm infants and respiratory failure in term neonates.ImpactKnowledge of how HFV works, how it influences cardiorespiratory physiology, and how to apply it in daily clinical practice has proven to be essential for its optimal and safe use.Therefore, we present important aspects of gas exchange, lung-protective concepts, clinical use, and possible adverse effects of HFV.The use of HFV in daily clinical practice in lung recruitment, determination of the optimal continuous distending pressure and frequency, and typical side effects of HFV are discussed.We also present study results on the use of HFV in respiratory distress syndrome in preterm infants and respiratory failure in term neonates.