Regulation of central and systemic stress response is in part controlled by the hypothalamo-pituitary-adrenal (HPA) axis. Adrenal steroids cross the blood brain barrier to act on the brain through nuclear receptors. In recent studies we described the intrinsic expression of corticosteroid-binding globulin (CBG) in rat and human brains. It is likely that known rapid effects of glucocorticoids (GCs) are mediated by non-genomic actions involving intrinsic binding globulins. CBG enhances bioavailability of systemic GCs thus increasing anti-inflammatory capacity and glucose utilization. A membrane receptor for CBG/GC has been postulated which in part could account for known non-genomic GC effects including the blockade of cytokine secretion. Intracellular CBG may be important for cytoplasmic steroid transport, for binding of GCs that are synthesized in the mitochondrial compartment, and for delivering GCs to cytosolic glucocorticoid receptors (GCR). CBG may be part of a complex cascade of central, systemic, membrane-based, cytoplasmic, mitochondrial, and nuclear events.