The brain is an important target organ for both endogenous and synthetic corticosteroid hormones, but the nature of steroid action there is complex. We review a series of studies that was designed to elucidate possible relationships between the behavioral and biological effects of exogenous corticosteroids. In these studies, corticosteroids were administered to intact animals or to currently healthy volunteers, and behavioral and biological indices of corticosteroid effects were jointly assessed. In the first study, chronic corticosterone administration to intact rats resulted in increased locomotor activity (consistent with increased caudate or nucleus accumbens dopamine activity) and increased caudate homovanillic acid (HVA) levels. In the second study, acute dexamethasone administration to healthy human volunteers resulted in increased plasma HVA levels. These findings in animals and humans may help explain vulnerability factors for experiencing psychotic reactions during chronic corticosteroid treatment. To more closely mimic clinical conditions in which "steroid psychoses" develop, we administered a higher dose and more chronic corticosteroid medication (prednisone, 80 mg/day for 5 days) in a double-blind manner to healthy volunteers. Consistent with prior clinical observations, behavioral changes were variable across subjects. Seventy-five percent of the individual volunteers developed mild behavioral side effects during prednisone administration; in addition, significant, specific deterioration in cognitive performance was observed. Prednisone administration was also associated with significant decreases in plasma levels of adrenocorticotropic hormone (ACTH), cortisol, and 3-methoxy,4-hydroxyphenyl glycol (MHPG) and in cerebrospinal fluid (CSF) levels of ACTH, beta-endorphin (BE), beta-lipotropin (BLPH), somatostatin-like immunoreactivity (SLI), and norepinephrine (NE). It was also associated with significant slowing of brain wave electrical activity (viz., an increase in theta wave activity) on quantitative electroencephalography. Several behavioral changes, particularly those relating to mood or cognition, were related to changes in CSF levels of NE, MHPG, ACTH, BE, BLPH, and SLI and to the slowing of brain wave activity. Our preliminary data raise the possibility that the behavioral effects of exogenous corticosteroids have specific neural concomitants and that the pattern of biological changes produced contributes to the behavioral variability observed. Steroid effects on levels of biogenic amines, pro-opiomelanocortin (POMC)-related peptides and somatostatin, among others, as well as on brain electrophysiology, may be behaviorally relevant and are highlighted as being worthy of further investigation.