CsA, FK-506, and rapamycin are microbial products with potent immuno suppressive properties that result primarily from a selective inhibition of T lymphocyte activation. Although chemically unrelated, CsA and FK-506 affect a similar subset of calcium-associated signaling events involved in the regulation of lymphokine gene expression, activation-driven T-cell death and exocytosis. Rapamycin has structural similarity with FK-506 but suppresses T-cell activation at a different level, mainly through inhi bition of proliferation induced by growth-promoting lymphokines. CsA interacts with an abundant 17 kDa protein, termed cyclophilin, that possesses peptidyl-prolyl cis-trans isomerase (PPIase) activity. Additional, minor cyclophilin-like molecules have been identified. Both FK-506 and rapamycin interact with FKBP, a 12 kDa protein, which, although unre lated to cyclophilin, is also abundant and ubiquitous, has a similar enzy matic activity, and is a member of a larger family of FKBPs. All three immunosuppressants inhibit the PPIase activity of their respective binding