The goal of this research project was to develop a novel method for mechanical ventilation, termed Multi-Frequency Oscillatory Ventilation MFOV, which optimizes gas exchange in the acute respiratory distress syndrome ARDS and other forms of combat-related lung injury, while simultaneously preserving mechanical protection of the lung. We hypothesized that lung function and gas exchange would be significantly improved if small volume oscillations are applied at multiple frequencies simultaneously, rather than at a single frequency, due to more even distribution of ventilation to different lung regions in accordance with local mechanical properties. In Specific Aim 1, we designed candidate MFOV waveforms for the acutely injured lung, using structurally explicit computational models of the mammalian respiratory system. Our simulations demonstrated that MFOV waveforms are capable of minimizing parenchymal strain and strain rate in healthy and injured lungs. In Specific Aim 2, we used dynamic Xenon-enhanced CT imaging and registration to establish that MFOV improves ventilation distribution and gas exchange in a porcine model of ARDS, compared to conventional modes of ventilation. The results obtained from these studies demonstrate that MFOV has a high likelihood of yielding a new, viable mode of ventilation for use in both military and civilian populations with ARDS.