The view of the endothelium as a passive barrier has gradually changed as a number of endothelium-derived substances have been discovered. Substances like nitric oxide, prostaglandins and endothelins have potent and important properties, involving not only the circulation as such but also the response to stimuli like inflammation and trauma. The endothelin system, discovered in 1988, has not only strong vasoconstrictor properties, but also immunomodulating, endocrinological and neurological effects exerted through at least two types of receptors. Septic shock, a condition with high mortality, is associated with vast cardiovascular changes, organ dysfunction with microcirculatory disturbances and dysoxia. In the experimental setting, endotoxaemia resembles these changes and is, as well as septic shock, accompanied by a pronounced increase in plasma endothelin levels. The pathophysiology in septic and endotoxin shock remains to be fully elucidated, but several studies indicate that endothelial dysfunction is one contributing mechanism. Activation of the endothelin system is associated with several pathological conditions complicating septic shock, such as acute respiratory distress syndrome, cardiac dysfunction, splanchnic hypoperfusion and disseminated intravascular coagulation. Through the development of both selective and nonselective endothelin receptor antagonists, the endothelin system has been the object of a large number of studies during the last decade. This review highlights systematically the findings of previous studies in the area. It provides strong indications that the endothelin system, apart from being a marker of vascular injury, is directly involved in the pathophysiology of septic and endotoxin shock. Interventions with endothelin receptor antagonists during septic and endotoxin shock have so far only been done in animal studies but the results are interesting and promising.