Stress response is the process that our body produces a series of nonspecific physiological and psychological response when dealing with pressure and danger. The hypothalamus - pituitary - adrenal (HPA) axis, as the central nervous system, plays a critical functional role in regulating stress response.Glucocorticoid receptor (GR) is an important regulatory factor for HPA axis’s homeostasis, and its function needs to combine with heat shock protein(Hsp90/70) and cochaperone proteins (FKBP51or FKBP52). FKBP51,a FK506-binding protein, is a negative regulatory of GR and HPA axis function. In recent years, Fkbp51 has been identified as a significant regulatory in the stress-related psychiatric and metabolic disorders. Here we will review the recent studies of Fkbp51on stress-related psychiatric and metabolic disorders.