A review of the generation and characterization of corticotropin-releasing hormone (CRH)-deficient mice is presented. The studies summarized demonstrate the central role of CRH in the pituitary-adrenal axis response to stress, circadian stimulation, and glucocorticoid withdrawal. Additionally, pro-inflammatory actions of CRH at sites of local inflammation are given further support. In contrast, behavioral effects during stress that had been ascribed to CRH action are not altered in CRH-deficient mice. The normal behavioral response to stress in CRH-deficient mice strongly suggests the importance of other, possibly as yet undiscovered, CRH-like molecules.