Acute respiratory distress syndrome (ARDS) is a common, devastating clinical problem arising from a number of conditions, such as pneumonia, trauma or sepsis. Because of its significant mortality and morbidity, ARDS has been in the focus of extensive experimental and clinical research. Since there is little doubt that alterations of the surfactant system contribute to lung dysfunction and the onset of ARDS, several clinical studies examined the therapeutic safety and efficacy of a surfactant replacement therapy. Clinical experience with exogenous surfactant has proven inconsistent as a therapeutic modality for adult patients with ARDS. This is mainly due to a number of confounding factors, e.g. severity of injury at the time of treatment, dosing regimes and delivery methods used in different trials. However, current data suggest that patients with direct ARDS (e.g. pneumonia, aspiration) could benefit from surfactant replacement therapy rather than patients with indirect ARDS (e.g. sepsis, trauma). Although surfactant replacement therapy has been shown to significantly reduce mortality in neonates with ARDS, there has been no large randomised clinical trial showing that exogenous surfactant improves outcome in adults with respiratory failure. Therefore, surfactant therapy cannot be recommended for routine clinical use in adult patients and has to be considered as a last resort treatment.