The interaction between the brain and the gut as a pathological mechanism of functional gastrointestinal disorders has been recently recognized in the pathophysiology of the irritable bowel syndrome. Communication between central nervous system and enteric nervous system is two-directional: the brain can influence the function of the enteric nervous system and the gut can influence the brain via vagal and sympathetic afferents. In patients with irritable bowel syndrome, symptoms may be caused by alterations either primarily in the central nervous system (top-down model), or in the gut (bottom-up model), or in a combination of both. The brain–gut axis may be stimulated by various stressors either directed to the central nervous system (exteroreceptive stress) or to the gut (interoceptive stress). Particularly, clinical evidence suggest that in complex and multifactorial diseases such as irritable bowel syndrome, psychological disorders represent significant factors in the pathogenesis and course of the syndrome. Neuroimaging techniques have shown functional differences between central process in healthy subjects and patients with irritable bowel syndrome. Moreover, a high prevalence of psychological/psychiatric disorders have been reported in IBS patients compared to controls. Several data also suggest an alteration of neuro-endocrine and autonomic output to the periphery in these patients. This review will examine and discuss the complex interplay of neuro-endocrine–immune pathways, closely associated with neuropsychiatric disorders.