The corticotropin-releasing factor (CRF) system plays a crucial regulatory role in the adaptation to exogenous and endogenous stress stimuli, as well as homeostasis. Apart from the central nervous system (CNS), the members of this neuropeptide family extend their actions in the periphery, where they may affect various body systems independently, stimulating peripheral CRF receptors via vagal and/or autocrine/paracrine pathways. Here, we review all findings concerning the expression and role of the CRF system in human liver, but also in other species. Direct and indirect regulatory data are also analyzed in order to draw conclusions about possible physiological/pathophysiological implications. Although data supporting any clinical significance are still limited and further research in the field is necessary, scientific interest in the CRF system is particularly active, with multiple ongoing clinical studies evaluating the activity of CRF ligands in medical conditions involving other organs. Thus, new knowledge with therapeutic potential appears to be steadily accumulating.