The effects of brief stressor exposure on hypothalamic-pituitary- adrenal (HPA) functioning was assessed in two strains of mice shown to be differentially responsive to stressors. Mild stress (1 min of cold swim, 20°C) led to marked elevations of plasma ACTH and corticosterone concentrations in the stress-reactive BALB/cByJ and the stress-resistant C57B1/6ByJ mice. Moreover, it was observed that the strains differed in basal CRH content within the amygdala and the paraventricullar nucleus (PVN). Within 1 min of cold swim, the CRH changes were detected in these brain regions in BALB/cByJ mice, but were less apparent in C57B1/6ByJ mice. Following a chronic stressor regimen, the marked elevations of plasma ACTH associated with acute stressors in BALB/cByJ mice were diminished. In contrast, in C57B1/6ByJ mice in which acute stressors hardly affected ACTH concentrations, the chronic stressor regimen lead to a marked increase of plasma ACTH. Taken together, data indicate that the stress reactivity differences seen in the two strains of mice are not limited to ACTH and corticosterone, but are also detected with respect to CRH within the amygdala and PVN. Furthermore, the suggestion is offered that the reactivity differences in the two strains of mice may have lead to different profiles of ACTH secretagogues and hence the response profile to later acute and chronic stressors differed in these strains of mice.