Lung injury can be initiated at birth with the delivery room resuscitation. Adequate tidal volume must be achieved gradually and adjusted with each subsequent breath to achieve adequate, but not excessive, tidal volume delivery. Time constants vary greatly within the lung because some alveoli are collapsed, and some are inflated. Excessive pressure or volume may lead to high stretch injury when already open alveoli are overdistended. Sufficient alveoli must be recruited to establish the optimal functional residual capacity. This establishes an inflation history of the lung that tends to resist alveolar collapse at the end of expiration, provided that adequate mean airway pressure is provided throughout the ventilatory cycle. The best volume of inflation is achieved at the lowest pressure cost. Maintaining alveolar recruitment with the use of exogenous surfactant and positive end-expiratory pressure avoids alveolar collapse and injury with succeeding distending breaths. Although there have been significant advances in neonatal respiratory care, further improvement in outcomes may be expected by successfully avoiding ventilator-induced lung injury.