Stress can be viewed as exposure of an animal to a hostile environment that compromises bodily homeostasis. Stress of this nature can occur in many forms, examples of which are extremes in environmental temperature, fear, predator attack and crowding. Elevation of heart rate, blood pressure, respiration rate and emotional agitation are among the many bodily manifestations of stress. In the gut, they can include diarrhea, constipation, incontinence, gastric regurgitation and gastrointestinal mucosal inflammation. Corticotropin-releasing factor (CRF) is a neuropeptide that plays a major role in the body’s overall responses to stress, including the gut. The physiology of central CRF signaling pathways in stress-induced changes in gastrointestinal motility and gastric acid secretion has been well characterized. Recent work elucidates how the physiology of peripheral CRF-related mechanisms contribute to stress-induced changes in gut motility and intestinal mucosal function. Acute stress, intramural CRF release and experimental application of selective CRF₁ receptor agonists evoke excitatory responses in neurons in the enteric nervous system (i.e., the brain-in-the-gut). Enteric neurons express CRF and its receptors. Exposure to acute and chronic stresses increases intestinal ion secretion and mucosal permeability to macromolecules and evokes diarrhea. Effects of stress on intestinal mucosal function are mimicked by peripheral injection of CRF and blocked by peripheral injection of non-selective peptide CRF receptor antagonists. CRF mRNA knock down in the enteric nervous system prevents intestinal responses to environmental stress in rodents. These findings constitute strong evidence that activation of peripheral CRF receptors in the enteric nervous system is a key mechanism involved in stress-related alterations of gut motility and mucosal function. In the cotton-top tamarin (Siquinus oedipus) model for ulcerative colitis and associated colon cancer, evidence suggests that environmental stress initiates the inflammatory response, which is then sustained by factors in the feces.