In this column, the authors first present a composite of several cases of psychiatrically healthy individuals who developed manic-depressive symptoms after receiving a course of prednisone to treat symptoms of inflammatory processes, such as Crohn's disease. The next section summarizes keys points from 50 years of clinical experience with such cases. The authors then present an overview of the effects of exogenous administration of glucocorticoids on cognitive performance and emotional processing via effects on medial temporal lobe and prefrontal structures, including the amygdala, hippocampus, and dorsolateral prefrontal cortex. These effects include glucocorticoid-induced deficits in declarative and autobiographical memory, altered activation of medial temporal lobe structures, and delayed habituation of hemodynamic responses to emotional faces. Finally, these findings are connected in a discussion of how glucocorticoid exposure can result in mood disturbances and what light that may shed on the neurobiology underlying spontaneous bipolar and unipolar affective illnesses.