The isolation of Cyclosporin A (CsA) from cultures of the fungus Tolypocladium inflatum and its subsequent elucidation of immunosuppressive properties by Borel et al. (1) was of great clinical consequence. In the early 80s CsA was introduced in the field of organ transplantation resulting in extraordinary improvements of graft survival. CsA has become a first choice drug for patients with allograft organs. The discovery of FK506 by Kino et al. (2) as a novel immuno-suppressant and its introduction into clinics in 1989 (3) extended the available regimen for immunosuppressive therapy. Yet despite their advantages both CsA and FK506 display unwanted side effects and a possible preference of one drug over another remains controversial (4, 5). Although identification of the involvement of the transcription factor NF-AT was an important step forward (6), it has become clear that immunosuppressant action is more complex. CsA and FK506 selectively interact with certain cellular signal transduction pathways. This review briefly describes these effects on signal transduction. We further concentrate on the major known effect of these immunosuppressants, namely the inhibition of the PP2B phosphatase calcineurin. In addition we provide a compilation of effects of CsA and FK506 on gene expression at the level of transcription.