In 1984, Gunther Fischer, a German biochemist studying protein folding, described an 18-kDa protein isolated from porcine kidney which catalyzed the interconversion of cis and trans rotamers of amide bonds adjacent to proline residues in peptidic substrates (Figure 1).1,2 Fischer termed this enzymatic activity peptidylprolyl cis-trans isomerase activity, and the enzyme became known as PPIase. In that same year, Handschumacher and colleagues investigating the cellular actions of the immunosuppressant drug cyclosporin A (CsA) (Figure 2) isolated a protein from calf thymus that was the principal binding protein for CsA.3 They dubbed this protein cyclophilin (CyP). By 1989, it became clear that PPIase and cyclophilin were the same protein.4,5 At the same time, Stuart Schreiber, as well as workers at Vertex Pharmaceuticals, reported the identification and characterization of the cytosolic binding protein for another immunosuppressant drug, the macrolide antibiotic FK506 (Figure 2).6,7 This protein also tightly bound the structurally related immunosuppressant drug rapamycin (RAPA). Although this new 12-kDa protein, called FKBP (for FK506 binding protein), had no sequence homology to cyclophilin, it too was shown to possess PPIase activity. All three drugs bound to the proline-binding site of their respective PPIase partners and potently inhibited their enzymatic activity. As it turns out, inhibition of PPIase activity is irrelevant for the immunosuppressive actions of CsA, FK506, and RAPA. It is the complex of the drugs with their cognate immunophilins that in each case is the active immunosuppressant species. As will be described in more detail shortly, the drug-immunophilin complexes interact with subsequent target proteins (the calmodulin-dependent phosphatase calcineurin in the case of FKBP/FK506 and CyP/CsA and the protein lipid kinase FRAP/RAFT in the case of FKBP/RAPA) to elicit immunosuppressive effects.8 Nonetheless, the finding that the biological activity of these two structurally distinct, clinically important classes of immunosuppressive drugs appeared to be mediated by two different proteins with a common enzymatic activity led to an explosion of interest and research on the PPIases. This research has demonstrated that cyclophilin and FKBP are each members of a large family of enzymes which are highly conserved and present in prokaryotic as well as eukaryotic organisms.9,10