The hypothalamic-pituitary-adrenal (HPA) axis plays a fundamental role in the response to stressful stimuli. Glucocorticoids (GCs), the most downstream effectors of the HPA axis, are the main mediators of the stress reaction. At the molecular level, GCs exert their function through binding to the intracellular glucocorticoid receptor (GR) which translocates into the nucleus to regulate gene transcription. The activation and action of GR is regulated via a dynamic multiprotein complex that includes the co-chaperone FK506 binding-protein 51 (FKBP51). Notably, abnormal FKBP51 function, arising from genetic variations or enhanced protein expression, and its impact on GR activity, have been widely related to stress-related diseases and to the response to antidepressant (AD) treatment. We have recently demonstrated the key role of FKBP51 SUMO attachment in the regulation of Hsp90-mediated inhibitory effect on GR activity. Taking this into consideration, we propose to study the role of ADs on SUMO conjugation to FKBP51 and its impact on GR activity. We aim that our research will shed light on novel aspects of GR modulation and provide new insights into molecular mechanisms related to depression.