How FKBP51 directly modulates GR has been investigated in vitro. In these systems, upregulation of FKBP51 decreases the affinity of GR for its substrate. This in turn decreases the amount of GR that becomes transcriptionally active. In new world monkeys a naturally occurring glucocorticoid resistance has been attributed to higher than normal levels of FKBP51. However, reduced GR activity in a transgenic mouse model of FKBP51 overexpression has never been shown. While the causes of major depressive disorders are unknown, there is an emerging genetic diathesis for its occurrence within genes regulating the HPA axis; however few animal models have been developed or utilized for aetiologic validation studies. Genetic variation in FKBP51 appears to be one factor that facilitates liability to anxiety and mood disorders. Thus, the goal of this study was to determine whether decreasing FKBP51 expression could make mice less susceptible to inducible ����depression-like���� states through a corticosterone-dependent mechanism in vivo in well established models with high predictive value. Indeed, aged FKBP5deficient mice were resistant to stress-induced depressive-like behavior. Moreover, despite robust hippocampal and forebrain expression patterns, deletion of FKBP5 did not result in cognitive impairment or other behavioral abnormalities. Circulating levels of corticosterone in the same FKBP52/2 mice were also reduced after stress, confirming the proposed mechanism previously described. These data suggest that not only is FKBP51 a valid therapeutic target, but targeting this protein may also have minimal consequences for other behavioral characteristics. Major depression is a devastating disease with a course that is frequently chronic or recurrent and affects millions of people. Research in the last decade has shown that variation in the FKBP5 gene is associated with depression and several other mood and anxiety disorders. And although in vitro data suggests the possibility of a causal relationship between FKBP5 expression levels and depression, this has never been tested in vivo. Here we show for the first time that ablation of FKBP5 in mice led to reduced immobility in two behavioral models that are routinely used to assess antidepressant efficacy. This behavioral effect coincided with attenuation of corticosterone production after a stressful episode. Moreover, no defects in locomotion, somato-sensation or learning and memory were observed. This isomerase activity is thought to be important for structural rearrangements and phosphorylation dynamics of client proteins bound by Hsp90. Several diseases in addition to psychiatric conditions have implicated FKBP51 as having a role in their pathogenesis. These include prostate cancer, and neurodegenerative diseases, specifically tauopathies.