Cyclosporine and FK506 are immunosuppressive drugs that have been extremely useful for treating graft-versus-host disease and autoimmune and inflammatory diseases, and they have truly revolutionized allograft transplantation. These drugs exert at least some of their immunosuppressive effects by blocking T-cell proliferation. Both drugs block T-cell proliferation by mechanisms that involve the inhibition of interleukin 2 production, a growth factor critical for T-cell proliferation. Recent studies, however, have shown that the effects of the drugs are not limited to blocking interleukin 2 production and that the production and the function of other molecules are also affected by these drugs. In this review, we examine recent studies on the molecular mechanisms of cyclosporine and FK506. © 2003 Elsevier Inc. All rights reserved.