Although significant advances in respiratory care have reduced mortality of patients with respiratory failure, morbidity persists, often resulting from iatrogenic mechanisms. Mechanical ventilation with gas has been shown to initiate as well as exacerbate underlying lung injury, resulting in progressive structural damage and release of inflammatory mediators within the lung. Alternative means to support pulmonary gas exchange while preserving lung structure and function are therefore required. Perfluorochemical (PFC) liquids are currently used clinically in a number of ways, such as intravascular PFC emulsions for volume expansion/oxygen carrying/angiography and intracavitary neat PFC liquid for image contrast enhancement or vitreous fluid replacement. As a novel approach to replace gas as the respiratory medium, liquid assisted ventilation (LAV) with PFC liquids has been investigated as an alternative respiratory modality for over 30 years. Currently, there are several theoretical and practical applications of LAV in the immature or mature lung at risk for acute respiratory distress and injury associated with mechanical ventilation.