In today's psychiatry there is a great deal of interest in the development of compounds with a novel mechanism of action that diverge from the classical catecholaminergic neurotransmitter system targets. Within the last few years, it has become increasingly evident that the neuroendocrine and behavioral phenotypes of mood and anxiety disorders are at least in part mediated by modulation of corticotropin-releasing hormone (CRH) neurocircuitries and that normalization of an altered neurotransmission after treatment may lead to restoration of disease-related changes. Although this concept was originally derived from peripheral hypothalamic-pituitary-adrenocortical (HPA) assessments in depressed patients, central CRH neuropeptidergic circuits other than those driving the peripherally accessible HPA system may be overactive and could be therapeutic targets of antagonist actions. Genetically engineered mice provide a novel and useful tool to study the endogenous mechanisms underlying aberrant behavior and CRH neurocircuitry regulation. The results obtained from conventional and conditional mutant mice indicate that CRH type 1 receptors may be the primary target to which to direct selective nonpeptide compounds. Moreover, beyond the encouraging preclinical studies, the first clinical open trial supports the notion that CRH type 1 receptors can be safely and effectively antagonized.