Corticotropin-releasing hormone (factor) family peptides (CRF peptides, CRFp) comprise four members, corticotropin-releasing hormone (CRH), urocortin (UCN1), UCN2, and UCN3, with CRH selectively acting on type 1 CRF receptors (CRFr)—CRF1, UCN1 on CRF1 and CRF2 (type 2 CRFr), and UCN2 and UCN3 on CRF2 (see Chaps. 2 and 3 ). After the finding of CRH in the brain by River and colleagues [1], CRH and UCNs are also found widely distributed in peripheral cells/tissues, including the digestive system [2, 3]. All these CRFp (CRH, UCN1, UCN2, UCN3) and their two distinct CRFr, CRF1 and CRF2, are observed to exist in the gastrointestinal tract (GI), both the upper and the lower part, and other digestive organs. Moreover, CRFp’s roles in GI have been well documented and the mechanisms may be complicated, sometimes difficult to differentiate between central and peripheral actions [4, 5]. For instance, peripheral use of UCN1 reduces feeding and induces interoceptive stress with increased cortisol level, while UCN2,3 suppresses feeding without inducing malaise in fasted and fed rats [6], suggesting the combined UCNs work on CRF1 and CRF2 in both central and peripheral ways, since central CRF1 activation is associated with stress and CRF2 activation suppresses feeding, and meanwhile, peripheral CRF2 activation also inhibits feeding by reducing GI motility [7]. This chapter will mainly focus on the peripheral distribution and effects of CRFp in digestive system, including actions directly on the digestive organs (GI tract, pancreas, and liver) and via the immune/inflammatory cells and enteric nervous system (ENS) influencing digestive functions.