Elevated circulating levels of glucocorticoids are associated with psychiatric symptoms across several different conditions. It remains unknown if this hormonal abnormality is a cause or an effect of the psychiatric conditions. For example, the hypercortisolemia observed in a subset of patients with depression may have a direct impact on the symptoms of depression, but it is also possible that the hypercortisolemia merely reflects the stress associated with depression. Further, rather than causing depression, hypercortisolemia could represent a homeostatic attempt to overcome glucocorticoid resistance. Each of these possibilities will be considered, and correlational and causal evidence will be reviewed. This article will focus on the relationships between glucocorticoids and psychiatric symptoms in Cushing's syndrome, major depression, and steroid psychosis/steroid dementia, as well as the effects of exogenously administered glucocorticoids in normal volunteers. Similarities and differences in the relationship of glucocorticoid hormones to psychiatric symptoms in these conditions will be reviewed. Possible mediators of glucocorticoid effects on the brain and behavior, as well as possible “pro-aging” effects of glucocorticoids in certain cells of the body, will be reviewed. The article concludes with a conceptual model of glucocorticoid actions in the brain that may lead to novel therapeutic opportunities.