Identification of the factors that regulate the immune tolerance and control the appearance of exacerbated inflammatory conditions is crucial for the development of new therapies of inflammatory and autoimmune diseases. Although much is known about the molecular basis of initiating signals and pro-inflammatory chemical mediators in inflammation, it has only recently become apparent that endogenous stop signals are critical at early checkpoints within the temporal events of inflammation. Some neuropeptides and hormones that are produced during the ongoing inflammatory response have emerged as endogenous anti-inflammatory agents that participate in the regulation of the processes that ensure self-tolerance and/or inflammation resolution. We will examine the latest research findings, which indicate that neuropeptides participate in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T cell effectors. We will also examine the role of some of these neuropeptides as mediators of innate defense acting as natural antimicrobial peptides. Both anti-inflammatory and pro-resolving neuropeptides have shown therapeutic potential for a variety of inflammatory and autoimmune disorders and could be used as biotemplates for the development of novel pharmacologic agents. From a physiological point of view, neuropeptides play a critical role in the innate-adaptive immune cross talk that allows survival.