A network of interconnected cell groups in the limbic forebrain regulate hypothalamic-pituitary-adrenal axis activation during emotionally stressful experiences, and disruption of these systems is broadly implicated in the pathophysiology of psychiatric illnesses.  Whereas abnormalities in prefrontal cortical function help to explain many of the cognitive and behavioral aspects of stress-related mental illnesses, dysregulation of this cortical region has emerged as a key player in mediating neuroendocrine alterations following chronic stress.  In this talk, evidence from our laboratory will be presented highlighting the neural mechanisms accounting for medial prefrontal cortical (mPFC) control over the HPA axis under acute stress conditions.  Next, the effects of chronic stress, glucocorticoids, and aging on structural plasticity in mPFC neurons will be described, with a discussion of how these alterations may lead to long-term behavioral and neuroendocrine consequences.