BACKGROUND Major depressive disorder is a serious and common psychiatric illness, and many of the depressive patients benefit from pharmacological treatment. Available antidepressants produce remission in only about 30 -- 40% of the patients. Therefore, new concepts are being explored for the development of innovative antidepressants with higher efficacy. METHODS The use of corticotropin releasing factor type 1 (CRF1) receptor antagonists for depression is supported by abundant evidence of target validation, the availability of in vitro and in vivo assays and specific small ligands. Some of these compounds have advanced to clinical studies, with discouraging results so far in depression. This review covers the development of CRF1 receptor antagonists at different stages of the development pipeline of the pharmaceutical industry and its bottlenecks. Most of the available CRF1 receptor antagonists known so far share a common chemical scaffold. We present possible strategies to overcome obstacles in the discovery and development process at the levels of library screenings and clinical studies to find more diverse compounds. CONCLUSIONS CRF1 receptor antagonists are expected to be beneficial only for those patients with CRF overexpression and the need for tests to identify these individuals is discussed. New technical developments and diagnostic tools might eventually lead to a more successful treatment of major depression with CRF1 receptor antagonists.