The permeability of endothelial surfaces increases in response to injury. We have shown that vascular leakage in experimental models of tissue injury can be inhibited by CRF and by a novel class of peptides that we call mystixins. Binding sites for iodinated-Tyro-CRF have been revealed in mucous membranes, and immunoreactive CRF-like materials have been found in inflamed tissues. Perhaps the breakdown of cytoskeletal intermediate filaments after insult generates or exposes peptide domains similar to mystixins. Endogenous CRF-like or mystixin-like peptides, if activated or released locally in injured tissues, may function as agonists to counteract the immediate inflammatory response. If this is so, the peripheral actions of these peptides add a new dimension to the idea that CRF and related substances organize and regulate an organism's response to stress.