High-frequency oscillatory ventilation (HFOV) is a lung-protective strategy that can be utilized in the full spectrum of patient populations ranging from neonatal to adults with acute lung injury. HFOV is often utilized as a rescue strategy when conventional mechanical ventilation (CV) has failed. HFOV uses low tidal volumes and constant mean airway pressures in conjunction with high respiratory rates to provide beneficial effects on oxygenation and ventilation, while eliminating the traumatic “inflate–deflate” cycle imposed by CV. Although statistical evidence supporting HFOV is particularly low, potential benefits for its application in many clinical manifestations still remain. High-frequency oscillation is a safe and effective rescue mode of ventilation for the treatment of acute respiratory distress syndrome (ARDS). All patients who have ventilator-induced lung injury (VILI) or are at risk of developing VILI or ARDS would be suitable candidates for HFOV, especially those who have failed conventional mechanical ventilation. This narrative aims to provide a review of HFOV vis-à-vis its indications, contraindications, hazards, parameters to monitoring, patient selection, clinical goals, mechanisms of action, controls for optimizing ventilation and oxygenation, clinical application in ARDS, and a comparison with other modes of mechanical ventilation.