A specific pulmonary surfactant becoming highly active on reduction of the surface area during expiration is responsible for the normal stability of lung expansion. The exact nature of this substance is not known, and therefore only activity, but not presence or concentration can be determined by three methods: (1) deflation characteristics of artificially inflated, intact lung specimens; (2) determination of surface tension of extracts or washings on a balance with a variable area; or (3) stability of air bubbles squeezed from lungs. The results of these methods correlate well, and the choice depends largely on technical considerations. The only spontaneous human disease in which a diffuse defect of stability occurs is the respiratory distress syndrome of newborn infants. Defects have been found under conditions produced in man by treatment, or in animals experimentally: prolonged pulmonary bypass, ligation of the pulmonary artery, atelectasis due to pneumothorax, or experimental pulmonary edema. It is not known whether in spontaneous or experimental deficiency of surfactant activity the active principle was either not produced, or chemically altered, or present but inactivated. This is of practical significance: if the surfactant were absent, one should introduce it therapeutically; if on the other hand, the surfactant were present but prevented from being active, knowledge of the factors influencing activity may be most important for rational therapy.