Gastrointestinal (GI) illnesses represent a paradigm of psychosomatic medicine. Nearly half of patients seen in GI practice present with functional illnesses, and patients commonly complain of symptoms that have coexisting organic and functional etiologies. This chapter addresses the connected nature of psychosocial factors and GI function, disease and outcome in the context of the biopsychosocial model, which allows illness to be examined from the encompassing perspective of interacting system, from the cellular to the environmental. This perspective also helps explain why biologic events such as oncogene alteration can produce heterogeneous clinical and biological responses. Links between gut and brain, involving neuroendocrine associations of the enteric nervous system and its connections with the spinal, autonomic and central nervous systems, are well documented. Neural connections allow information to affect GI secretion and motility. Disturbances in one component of the system can lead to brain-gut effects, such as dysmotility and mood disturbance. Appropriate diagnosis and treatment require clear understanding of biologic, psychologic, and social contributory events. In chronic unexplained GI illnesses, the appropriate clinical approach may be to suspend the search for structural disease, and work instead to assess and treat the physical symptoms and psychosocial problems at hand.