Aversive life events represent one of the main risk factors for the development of many psychiatric diseases, but the interplay between environmental factors and genetic predispositions is still poorly understood. One major finding in many depressed patients is an impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The negative feedback loop of the HPA axis is mediated via the glucocorticoid receptor (GR) and the mineralocorticoid receptor. The co-chaperones FK506-binding protein 51 (FKBP51) and FK506-binding protein 52 (FKBP52) are components of the heat shock protein 90-receptor-heterocomplex and are functionally divergent regulators of both receptors. Here, we characterized heterozygous Fkbp52 knockout (Fkbp52(+/-)) mice under basal or chronic social defeat stress (CSDS) conditions with regard to physiological, neuroendocrine, behavioral and mRNA expression alterations. Fkbp52(+/-) mice displayed symptoms of increased stress sensitivity in a subset of behavioral and neuroendocrine parameters. These included increased anxiety-related behavior in the elevated plus-maze and an enhanced neuroendocrine response to a forced swim test (FST), possibly mediated by reduced GR sensitivity. At the same time, Fkbp52(+/-) mice also demonstrated signs of stress resilience in other behavioral and neuroendocrine aspects, such as reduced basal corticosterone levels and more active stress-coping behavior in the FST following CSDS. These contrasting results are in line with previous reports showing that FKBP52 is not involved in all branches of GR signaling, but rather acts in a gene-specific manner to regulate GR transcriptional activation.