Communication and reciprocal regulation between the nervous, endocrine and immune systems are essential for the stability of the organism. Among others, cytokines, hormones and neuropeptides have been identified as signalling molecules mediating the communication between the three systems. This review focuses on the role of the neuropeptide somatostatin as an intersystem signalling molecule, with emphasis on the immune system. Somatostatin down-modulates a number of immune functions, among others lymphocyte proliferation, immunoglobulin production and the release of proinflammatory cytokines such as IFN-g. Systemic or local treatment with somatostatin or somatostatin analogues has been shown to be beneficial in a number of in vivo models of autoimmune disease and chronic inflammation. In many of these models somatostatin appears to antagonise the effects of another neuropeptide, substance P. A somatostatin-substance P immunoregulatory circuit has been proposed to operate within murine Schistosoma mansoni-induced granulomas. In this review we extend the model of the somatostatin-substance P immunoregulatory circuit to include data derived from other biological systems, and those relying on human clinical situations. In addition, we present a hypothesis on the regulation of the default class of immune response within a tissue, based on the local balance of pro-and anti-inflammatory neuropeptides.