In addition to their clinical utility in tissue transplantation the immunosuppressive agents FK-506 (Prograf) and rapamycin, have proven to be valuable tools for gaining insight into the biochemistry of T-cell activation. The findings that the protein phosphatase calcineurin and cell cycle control are key elements in T-cell activation and proliferation are the direct result of investigations into the mechanism of action of FK-506 and rapamycin and provide potentially novel therapeutic targets.