Major depressive disorder (MDD) is characterized by a dysregulation of the stress response system. A corticotropin-releasing factor (CRF) hyperdrive is a consistent and well-documented finding. CRF-binding protein (CRF-BP) may play a role in the pathogenesis of MDD. CRF-BP reduces the availability of CRF by binding free CRF and inhibits CRF function at the pituitary level. Moreover, CRF-BP expression increases in the pituitary and amygdala in response to acute stress, providing an additional feedback mechanism to maintain the homeostasis of the stress response. There are different regulatory elements of the expression of CRF-BP gene that are implicated in the pathophysiology of MDD, including CRF, glucocorticoids, cytokines and estrogens. A specific haplotype within the CRF-BP gene has been associated with MDD, but confirmation of this finding is necessary. Currently, the possible role of CRF-BP in the pathophysiology of conditions that have been associated with a hypofunction of the CRF system and immune dysfunctions is unclear. Implications of the function of CRF-BP for therapeutic strategies in MDD are being discussed. An important advantage of ligands that target CRF-BP is that concentrations of free CRF can be altered without acting directly on the transmission of CRF through its receptor.