The loss of immune tolerance results in the breakdown of immune homeostasis and the appearance of exacerbated inflammatory conditions. Some anti-inflammatory neuropeptides have recently emerged as endogenous factors participating in the maintenance of immune tolerance. The effects of these neuropeptides in self-tolerance primarily depend on the activation of cAMP-protein kinase A signaling and the regulation of various transduction pathways involved in the expression of many immune factors. Understanding of the structure-function relationship of anti-inflammatory neuropeptides and their receptors will facilitate the development of novel pharmacological agents for the treatment of immune disorders.