It has been increasingly appreciated that an intimate interaction between cells of the nervous and immune systems takes place in the gut, and may have a role in diverse inflammatory disorders. Thus, for instance, activation of the enteric nervous system may reduce intestinal epithelial permeability, via several mediators including S-nitrosoglutathione and vasoactive intestinal peptide (VIP). Moreover, ablation of glial cells instigated enterocolitis in murine models. These neuronal effects are particularly intriguing given our current understanding of the immunopathogenesis of Crohn's disease, in which intestinal barrier defect is suspected to at least partly drive the immune hyper-reactivity and ensuing inflammation. Parasympathetic nicotinic signaling, primarily via nicotinic acetylcholine receptor alpha7 (alpha7 nACHr), also exerts immunomodulatory effects, possibly underlaying the detrimental effects of smoking on Crohn's disease, and its beneficial impact on ulcerative colitis. These, and others, neuro-immune interactions may pave the way to the design of novel therapeutic agents for the treatment of chronic inflammatory bowel disorders.