Although the lack of ACTH releasing activity of the high peripheral plasma levels of corticotropin releasing factor (CRF) of human placental origin can now be accounted for by the action of a specific sequestering plasma binding protein (pBP), there are many regions of the brain where the BP is found with little or no overlap with CRF. The existence of a mechanism promoting the rapid disappearance of pBP following bolus injection of exogenous CRF into normal individuals, which is triggered by the formation of a dimer complex (BP2/CRF2), and the elevation of pBP levels found in inflammatory disease, coupled with the lack of unequivocal evidence for endogenous CRF in many of these situations, suggests a role for pBP interaction with ligands other than CRF. We have searched for novel BP ligands in the brain and periphery and have found evidence for them in extracts of sheep brain and in synovial fluid collected from the joints of arthritic patients. These novel BP ligands could, thus, be the peptides responsible for many of the roles currently assigned to brain, peripheral, or immune CRF.