Abstract: The term immunophilin involves a family of proteins whose domain shows peptidyl-prolyl-(cis/trans)-isomerase (PPIase) enzymatic activity, i.e., the reversible cis/trans interconversion of Xaa-Pro bonds (Annett et al., 2020). The PPIase domain of these proteins usually binds to immunosuppressive drugs, such as the macrolide FK506 (referred to as the FKBP subfamily) or the cyclic undecapeptide cyclosporine A (called CyP subfamily). The binding of the drug implies the inhibition of the PPIase enzymatic activity. Those members of each subfamily that show the smallest molecular weight (i.e., FKBP12 and CyP17/CyPA) are the only proteins responsible for the immunosuppressive action of the cognate drug due to the abrogation of calcineurin (or protein-phosphatase 2B) biological action. This prevents the nuclear translocation of phospho-NFAT, a transcription factor that induces the expression of interleukins and interferon-γ, both factors being critical components of the cell-mediated immune response. In contrast to those two low molecular weight immunophilins, larger members of the family such as the heat-shock protein of 90 kDa (HSP90)-binding immunophilins are not related to immunosuppression and are characterized by the additional presence of degenerate sequences of 34 amino acids repeated in tandem arrays, the TPR domains, through which they interact with dimers of the molecular chaperone HSP90 and the associated cochaperone p23 (Figure 1A).  Among them, FKBP51 and FKBP52 are studied well since they were first described associated with the HSP90-based chaperone heterocomplex of steroid receptors (Storer et al., 2011). Both immunophilins share 75% of amino acid similitude and bind FK506 with equivalent Ki. They play regulatory roles in the steroid-dependent retrotransport of corticosteroid receptors, the translocation of the receptor through the nuclear pore complex, and the hormone-dependent transcriptional regulation (Zgajnar et al., 2019; Mazaira et al., 2020). Usually, both immunophilins show antagonistic action. Thus, FKBP52 favors glucocorticoid binding to the glucocorticoid receptor as well as the active transport of glucocorticoid receptor and other factors (NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; hTERT, human telomerase reverse transcriptase; p53, tumor protein of 53-kDa) throughout the cytoplasm to the nucleus using dynein/dynactin motors to power that movement. The motor complex interacts with the PPIase domain of FKBP52, but not with that of FKBP51 (Storer et al., 2011). In addition to its role in protein trafficking, FKBP52 also enhances the steroid-dependent transcriptional activity of steroid receptors and NF-kB, whereas its partner FKBP51 shows inhibitory effects (Lagadari et al., 2016; Daneri-Becerra et al., 2019). In the nervous system, the expression of FKBP51 and FKBP52 is noteworthy in both neurons and glial cells.