Basic and clinical studies demonstrate that the central corticotropin-releasing hormone (CRH) circuits are overactive among depressives, a phenomenon frequently reflected by enhanced cortisol and corticotropin levels in the peripheral blood of these patients. Behavioral pharmacology provided evidence that CRH overexpression accounts for many signs and symptoms characteristic of depression. CRH-type 1 receptors (CRHR), were identified as responsible for conveying the CRH signal into cellular circuitries, thereby inducing depression-related symptoms. In order to decrease CRH signaling, many pharmaceutical companies have developed small molecules that after oral ingestion, penetrate the blood-brain barrier and selectively bind at CRHR1 with high affinity. These compounds have been tested in animal models and patients with major depression. One of these compounds, R-121919 (Neurocrine Biosciences Inc), ameliorated depressive symptomatology without unwanted endocrine side effects or other adverse effects. While clinical trials of R-121919 have been discontinued after phase IIa studies, a number of other CRHR1 antagonists are being developed, and hopefully this advance will ultimately lead to a favorable alternative to currently available antidepressant drugs.