Swelling, oedema, and loss of fluids and protein from the vascular compartment are immediate responses seen in living tissues after severe injury. Peptides of the corticotropin-releasing factor (CRF) superfamily have the unusual property of preventing the vascular leakage that occurs in tissues after damage. For example, CRF decreased protein extravasation, oedema and swelling in the anaesthetized rat's paw after exposure to heat or to extreme cold, in tracheal mucosa after exposure to formaldehyde, in skeletal muscle after a knife cut, and in brain cortex after freezing. The anti-inflammatory actions of CRF were independent of steroid release or hypotensive effects. CRF was a functional antagonist of inflammatory mediators such as histamine and substance P. It inhibited neurogenic inflammation, but interactions with unmyelinated sensory neurons did not account for the wide range of CRF's anti-inflammatory activities. Localized application of CRF prevented histamine-induced leaks in the hamster cheek pouch, and displaceable binding sites to iodinated CRF were found on blood vessels and on epithelial cells in close proximity to sites of vascular leakage. These results indicated peripheral sites of action. CRF may be the first example of a peptide hormone demonstrated to have potent anti-inflammatory agonist actions in vivo.