The hypothalamic-pituitary-adrenal (HPA) axis plays a fundamental role in the response to external and internal stimuli. Activation of the HPA axis is a tightly controlled process that involves the neuroendocrine system. Glucocorticoids (GCs), the most downstream effectors of the HPA axis, are the main mediators of the stress reaction. Among their wide range of biological actions, GCs play a prominent role in regulating the magnitude and duration of the HPA axis activation. Following exposure to stress, elevated levels of circulating GCs inhibit HPA activity. At the molecular level, GCs exert their function through binding to the intracellular glucocorticoid receptor (GR). Regulation of target gene expression by activated GR includes the recruitment of coregulators, which in many cases are modifiers of chromatin structure, pointing to the role of stress-elicited GCs in mediating epigenetic modifications. Upon ligand binding, the activation and action of GR is regulated via a dynamic multiprotein complex that includes the co-chaperone FK506 binding-protein 51 (FKBP51). Notably, altered FKBP51 expression is associated to impaired GR activity and depressive disorders.Taking this into consideration, we propose to study the impact of the posttranslational small ubiquitin-like modifier (SUMO) conjugation to FKBP51 on its activity as a GR co-regulator and its impact on GR-mediated epigenetic modulation of target genes. We aim that our research will shed light on novel aspects of GR modulation and provide new insights into molecular mechanisms possibly related to depression.