Lung surfactant deficiency and dysfunction contribute to the pathophysiology of several important respiratory diseases. The major disease of lung surfactant deficiency worldwide is the respiratory distress syndrome (RDS) of premature infants, also called hyaline membrane disease (HMD). Developing clinically effective exogenous surfactant therapy for RDS has been a major driving force in lung surfactant research. A second, much more rare form of surfactant-deficient lung disease occurs when a functional component of lung surfactant is not produced. This is the case in hereditary SP-B deficiency, a genetic disease associated with lethal respiratory failure in infants. The most important conditions associated with surfactant dysfunction are acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Surfactant deficiency can also occur in ALI and ARDS, but dysfunction from biophysical or chemical interactions with inhibitors is typically more prominent. The complex pathophysiology of acute lung injury and ARDS described in this chapter presents a significant challenge for surfactant replacement interventions.