Depression is a highly prevalent form of mental illness. This condition is often considered a stress-related disorder because some form of stressful life event frequently triggers depressive symptoms. Corticotropin-releasing factor (CRF) is a 41 amino acid neuropeptide involved in mediating neuroendocrine, autonomic and behavioral responses to environmental demands, and has long been considered one of the bodys major regulators of the stress response. Results from clinical studies suggest that normal functioning of the CRF system is altered in patients diagnosed with depression. Two genes encoding distinct G-protein coupled CRF receptors have been identified, the CRF1 receptor and CRF2 receptor. Originally, the belief was that activation of the CRF system would lead to increases in the stress response. Recent characterization of the CRF receptor subtypes and CRF receptor specific ligands, however, suggests that there may be a differential regulation of stress within this system and that imbalances in receptor activation could lead to the development of stress-related psychiatric disorders. Preclinical models show evidence for increased CRF1 receptor activity in the regulation of depressive-like behaviors, and a number of nonpeptide CRF1 receptor antagonists have recently been developed as potential antidepressant medications. Although, the role of CRF2 receptors remains unclear in depression, preclinical evidence suggests that under activation of this receptor may be involved in the regulation of increased depression-like behavior in animals. The present article will review the role of CRF receptors and CRF-related ligands in depression and proposes targeting the CRF system as a potential pharmacotherapy for depressive disorders.