Unliganded steroid receptors for progestins (PR) glucocorticosteroids (GR), oestrogens (ER), androgens (AR) and mineralocorticosteroids (MR) are recovered from target tissue homogenates in large heteromeric complexes containing heat shock proteins (namely hsp90 and hsp70), immunophilins (Ips) and other proteins. Among these Ips, two ubiquitous and well conserved FK506 binding proteins, FKBP51 and FKBP52, and one Cyclosporin A (CsA) binding Ip (CYP40) have been identified. Each of them interacts with hsp90 (in a competitive manner) via a C terminal tetratricopeptide sequence, forming separate complexes containing one receptor molecule. Ips are peptidyl prolyl cis/irans isomerases (PPIases), the activity of which is inhibited in vitro by immunosuppressant binding. Although highly structurally related, FKBP51 and FKBP52 behave differently in vitro as well as in vivo; whereas FKBP51 dissociates rapidly from the PR and GR heteromeric structure following progestin and glucocorticosteroid binding, the FKBP52 does not. In addition, the interaction of this latter protein with both receptors is reinforced by the immunosuppressant rapamycin in vitro as well as in vivo. FKBP52 is also thought to be involved in the glucocorticosteroid-induced nuclear translocation of the GR, and it could be a nuclear localization signal binding protein. Numerous reports have established that phosphorylation/ dephosphorylation mechanisms regulate steroid-induced signal transduction; since Ips are known to participate in several signaling pathways implying phosphatase and/or kinase activities, attempts are made to decipher those in which Ips and steroid receptors are involved. In this review, we take stock of possible Ips-mediated mechanisms which may alter the steroid response and consider the possibility that they could act as regulators of steroid-mediated transcription.