Depressive disorders are a leading cause of morbidity and mortality worldwide. Current antidepressant drugs targeting monoamine neurotransmitter systems have a delayed onset of action, and fewer than 50% of the patients attain complete remission after therapy with a single antidepressant. A large body of preclinical and clinical evidence points to a key role of the corticotropin-releasing hormone (CRH) receptor 1 subtype (CRHR1) in mediating CRH-elicited effects in anxiety, depressive disorders and stress-associated pathologies. Genetic modification of CRHR1 function in mice by the use of conventional and conditional knockout strategies enables further analysis of specific elements in the CRH circuitry. The recent characterisation of several selective small-molecule CRHR1 antagonists offers new possibilities for the treatment of anxiety and depression.