Acute respiratory distress syndrome (ARDS) is a clinical syndrome affecting both medical and surgical patients which frequently necessitates mechanical ventilation in an intensive care unit and carries considerable morbidity and mortality. At present, there is no treatment specifically directed at the underlying pathophysiology. Central in its pathophysiology is the inflammation-induced activation of coagulation, and the resulting depletion of naturally occurring anticoagulants.; This narrative review is based on a PubMed search of relevant clinical studies published in English and discusses the role of systemic administration of activated protein C, antithrombin, tissue factor pathway inhibitor, inactivated factor VIIa and heparin in the treatment of ARDS. Clinical trials of systemic anticoagulant strategies in ARDS patients have proven unsuccessful in improving patient outcomes. We suggest some future directives. © 2014, Nederlandse Vereniging voor Intensive Care.