Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with vulnerability to a number of psychiatric diseases including major depression, bipolar disorder, anxiety disorders, and schizophrenia. The HPA axis is activated in response to stress and in a characteristic circadian rhythm, resulting in the release of glucocorticoid hormones from the adrenal cortex. These hormones act on peripheral target tissues to restore homeostasis to the organism and engage glucocorticoid receptors (GR) in the CNS to control the intensity and duration of the stress response. Alterations in this glucocorticoid sensing system may underlie the HPA axis changes associated with psychiatric disorders. Recently, a number of lines of mice with genetically altered GR signaling in the CNS have been generated to address this hypothesis. Here, we summarize findings from new genetic models that indicate a critical role for GR signaling in the CNS in normal regulation of the HPA axis and behavioral/emotional stability.