Prioritizing lung-protective ventilation has produced a clear mortality benefit in neonates with congenital diaphragmatic hernia (CDH). While there is a paucity of CDH-specific evidence to support any particular approach to lung-protective ventilation, a growing body of data in adults is beginning to clarify the mechanisms behind ventilator-induced lung injury and inform safer management of mechanical ventilation in general. This review summarizes the adult data and attempts to relate the findings, conceptually, to the CDH population. Critical lessons from the adult studies are that much of the damage done during conventional mechanical ventilation affects normal lung tissue and that most of this damage occurs at the low-volume and high-volume extremes of the respiratory cycle. Consequently, it is important to prevent atelectasis by using sufficient positive end-expiratory pressure while also avoiding overdistention by scaling tidal volume to the amount of functional lung tissue rather than body weight. Paralysis early in acute respiratory distress syndrome improves outcomes, possibly because consistent respiratory mechanics facilitate avoidance of both atelectasis and overdistention—a mechanism that may also apply to the CDH population. Volume-targeted conventional modes may be advantageous in CDH, but determining optimal tidal volume is challenging. Both high-frequency oscillatory ventilation and high-frequency jet ventilation have been used successfully as ‘rescue modes’ to avoid extracorporeal membrane oxygenation, and a prospective trial comparing the two high-frequency modalities as the primary ventilation strategy for CDH is underway.