Corticotropin-releasing factor (CRF) has been implicated in endocrine and behavioral responses associated with stress. We have now studied the behavior of mice lacking the CRF gene (CRFko), comparing them to wild-type (WT) mice. Behaviors were observed in untreated mice, as well as following restraint or intraperitoneal administration of mouse interleukin-1beta (mIL-1beta). In the multicompartment chamber (MCC), the behaviors of CRFko and WT mice were very similar, and prior restraint and IL-1beta induced similar decreases in stimulus-contact times in both genotypes. In the elevated plus maze (EPM), restraint decreased the number of open arm entries but the behavior of both genotypes was very similar. In the open field (OF), the changes in locomotor activity in response to restraint were similar in both genotypes, although CRFko mice displayed slightly increased locomotor activity compared to WT mice. In both the MCC and the EPM, grooming behavior was increased by restraint, and was higher in the CRFko than in the WT mice. Compared to WT mice, CRFko mice had lower basal plasma concentrations of corticosterone which did not increase significantly following footshock. Thus, CRFko mice showed a clear dichotomy; the stress-related activation of the hypothalamo-pituitary-adrenal (HPA) axis was absent, whereas the stress-related behavioral responses thought to be mediated by brain CRF were unaffected. These results suggest that when mice develop in the absence of CRF, another factor (or factors) assumes the behavioral functions normally ascribed to brain CRF, but not activation of the HPA axis. Alternatively, the natural modulator of behavior may not be CRF, but some other molecule that can act on receptors sensitive to CRF. Thus, redundant CNS mechanisms appear to be involved in stress-related behaviors.