Data in favor of the hypothesis of the common evolutionary origin of natural immunity inflammation and stress response are presented. These phenomena seem to be mediated by a common pool of molecules (POMC-derived peptides, cytokines, biogenic amines, glucocorticoids, and nitric oxide). Macrophages are able to release all the above mentioned molecules. They play a primary role in defence mechanisms. Thus, we argue that this cell can be considered the eye-witness of the common evolutionary origin of the immune and neuroendocrine systems.