Of all of the efflux pumps highly expressed in the BBB P-glycoprotein (P-gp, MDR1) handles the largest fraction of commonly prescribed drugs. Despite that knowledge, little is known about its endogenous substrates. Introduction of the P-gp double knock-out mouse (mdr1a/b -/-) by A. Schinkel showed normal viability and no characteristic phenotype of such mice (Schinkel et al., PNAS 1997:94;4028–33). However, there were some indications that P-gp is involved in the modulation of the hypothalamic-pituitary-adrenocortical (HPA) system. We investigated the role of P-gp on stress-related phenotype in several behavioral tasks. P-gp knock-out mice (mdr1a/b -/-) were compared to wildtype FVB/N in ethological paradigms and displayed a clear phenotype related to novelty and stress. It is hypothesized that in knock-out animals stress response is blunted due to an altered access of corticosterone into the brain, supported by quantification of corticosterone levels in the brain of both genotypes. Results of administration of corticosterone and metyrapone, a corticosterone synthesis inhibitor, in knock-out and wildtype mice gave strong in vivo evidence that P-gp plays a substantial role in mediation of stress response and thus medication affecting P-gp might affect stress response as well. To our knowledge present data were the first, showing a clear phenotype for P-gp deficient mice and give evidence for a clinical relevance of BBB efflux pumps in stress related diseases.