Conventional strategies for protective mechanical ventilation in injured lungs rely on positive end-expiratory pressure to limit derecruitment and low tidal volumes or driving pressures to limit overdistention. In injured lungs, it has been demonstrated that using multiple superimposed frequencies, termed “multi-frequency ventilation” (MFV), results in a more even ventilation distribution consistent with regional mechanical properties. In this presentation, Dr. Kaczka will discuss the theoretical rationale for using MFV in structurally heterogeneous acute lung injury and demonstrate the mechanisms by which MFV improves regional ventilation distribution, aeration, and lung parenchymal strain. The assessments are based on dynamic xenon-enhanced computed tomographic imaging and four-dimensional image registration. These pre-clinical studies of MFV may establish the foundation for further explorations of novel ventilation modalities in a broad range of patients with acute respiratory failure.