In the past years, the influence of psychosocial and environmental stressors in different pathogenesis received increased awareness. The brain is the master manager of the interpretation of what is stressful and of the physiological responses that are produced. Animals have developed conserved strategies to respond to stressful conditions, in particular, the secretion of stress-specific neuromediators which mediate protective and adaptative effects in the short run and yet can accelerate pathophysiology when they are over-produced or mis-managed. The Cortico-Releasing Factor (CRF) and their derived peptides are the majors stress neuromediators. Their localization has originally been described in the central nervous system where they play a pivotal role to activate the hypothalamic-pituitary-adrenal (HPA) axis and was recently extended to the periphery. While the peripheral effects of CRF signalling need to be more thoroughly investigated, it has been described to influence disease negatively, in particular in the intestine. The epithelial barrier is a crucial checkpoint to control body entrances. Prolonged exposure to stress can cause ultrastructural epithelial abnormalities and can increase barrier permeability, which favors luminal translocation, immune activation and thus induces inflammation. This review summarizes the present knowledge on the stress response and the effects of both acute and chronic stress to induce pathological damages to the intestine. We present the potential pathways involved, and the proposed mechanisms of action, mediating these effects. The CRF system is potentially useful as a diagnostic marker or a therapy target for inflammatory diseases and cancer.