Although the treatment of multiple-injured patients has been improved during the last decades, sepsis and multiple organ failure (MOF) still remain the major cause of death. Following trauma, profound alterations of a large number of physiological systems can be observed that may potentially contribute to the development of sepsis and MOF. This includes alterations of the neuroendocrine and the immune system. A large number of studies focused on posttraumatic changes of the immune system, but the cause of posttraumatic immune disturbance remains to be established. However, an increasing number of data indicate that the bidirectional interaction between the neuroendocrine and the immune system may be an important mechanism involved in the development of sepsis and MOF. The aim of this article is to highlight the current knowledge of the neuroendocrine modulation of the immune system during trauma and sepsis.