Despite improvements in respiratory care, ventilator-induced lung injury remains an important cause of morbidity and mortality in neonates who require assisted ventilation. Animal data clearly demonstrate that high-frequency ventilation can be used successfully to reduce lung injury in experimental models of acute lung injury. These models and human research show that the efficacy of high-frequency ventilation is dependent on optimizing functional residual capacity and avoiding lung overinflation. When used with a strategy that promotes lung recruitment, high-frequency ventilation effectively reduces the occurrence of chronic lung disease and is not associated with significant brain injury. When used with a strategy that allows the lung to collapse or is associated with hyperventilation, however, high-frequency ventilation does not reduce lung injury and is associated with significant brain injury. Like every tool we use to support critically ill neonates, high-frequency ventilation needs a careful carpenter. As therapies and health care strategies evolve, there remains nothing more important than the health care team at the bedside. Critical evaluation of the patient and his or her response to the therapy being offered is essential to promotion of the patient health outcome.