The use of perfluorochemical (PFC) liquids to facilitate or support respiration has been under study for several decades. The low surface tension and high respiratory gas solubility of liquid PFC enable adequate oxygenation and carbon dioxide removal at low insufflation pressures relative to gas ventilation in the immature or injured lung. Because liquid ventilation homogeneously inflates the lung and improves V/Q matching it has been studied as a vehicle for delivering biologically active agents to the lung tissues and systemic circulation. More recently, we have shown the utility of highly opaque PFC liquids as a high resolution computed tomographic (HRCT) bronchographic contrast agent either during LV or gas breathing after tracheal instillation of small quantities of PFC. As a result of extensive experimental work in premature animals as well as lung injury models, liquid PFC ventilation has been recently implemented as an investigational therapy for severe respiratory distress in human infants. This manuscript summarizes the physiological principles and applications of LV as well as the results of initial investigational clinical studies in human neonates with severe respiratory distress.