Endothelins (ETs) are multifunctional isopeptides and their role in several pathophysiologies is slowly emerging. They are possible therapeutic targets in sepsis and other systemic inflammatory response syndromes (SIRS). In such conditions, elevated concentrations of ETs have been reported, together with other proinflammatory markers such as several cytokines. Some of the cytokines even modulate the expression, production, and release of ETs from cells and also the biological responsiveness of ETs into the circulation. Here, we systematically review the literature and discuss the role of these peptides in affecting vascular and inflammatory responses in SIRS. This review also intends to provide a better understanding of the mechanisms of ETs and their interrelationships to other mediators, mainly cytokines, in SIRS. There is no doubt that ETs are useful markers of vascular injury in SIRS. From experimental evidence in animals, endothelins, as potent vasoconstrictors, play a beneficial central compensatory role against the loss of vascular tone associated with SIRS. Conversely, endothelins compromise the circulation in several vascular beds and exacerbate conditions in which inadequate perfusion already exists during the early stages of SIRS. Since no single magic solution has been found for complex diseases related to SIRS, we should look toward a group of mediators, such as cytokines and endothelins, acting as team players.