Altered behavioral responses to stressors have been observed in animals exposed to cocaine prenatally. In the present study, both behavioral and physiological responses to repeated and single stressor exposure were measured in animals prenatally exposed to cocaine. Offspring were derived from 3 prenatal treatment groups: dams that were administered 40 mg/kg cocaine from gestational day 8-20 (C40); dams that were pair-fed and -watered to weight-matched C40 dams (PF); and untreated dams (LCC). Starting on postnatal day 16-17 (P16-17), offspring from the 3 prenatal treatment groups were exposed to either footshock or isolation daily for 5 days. Two days after the last day of stressor exposure (P21-22), subjects were given 1 final exposure to the stressor to which they were previously exposed. In addition, at P21-22, littermates of animals given repeated exposure to stressors were exposed to either footshock or isolation for the first and only time. During all footshock sessions, the duration of freezing behavior was recorded. Plasma adrenocorticotrophin (ACTH) and corticosterone levels were determined from blood samples taken immediately following the final stressor session and brains were processed for C-FOS immunoreactivity (FOS-IR). Plasma corticosterone was increased following either single or repeated exposure to either stressor compared to homecage control animals. Plasma ACTH was increased by exposure to both repeated and single footshock exposure, but the increase was not as great following repeated footshock exposure, suggesting adaptation to repeated exposure to this stressor. Following both single and repeated footshock exposure, FOS-IR was increased relative to baseline levels in the paraventricular nucleus of the hypothalamus (PVN) and in the supraoptic nucleus (SON), but not the locus coeruleus (LC). Repeatedly footshocked animals exhibited more time freezing than animals given a single footshock session. Prenatal exposure to cocaine resulted in more time spent freezing in C40 than LCC animals during the chronic footshock exposure period; however, no differences were seen in any of the physiological measures taken from these 2 groups on the final test day. The implications of these findings are discussed in the context of other research examining the effects of prenatal cocaine exposure on stress responses.