Recent progress in understanding of the pathophysiologic mechanisms of an increasing number of diseases involving immunologic effector mechanisms and the broadening of indications for allograft transplantation have considerably expanded the use of immunosuppressive drugs in clinical medicine. A new therapeutic situation has thus been created that reproduces various aspects of pathologic conditions such as primary and secondary immunodeficiency disorders. This increasing use of immunosuppressive drugs raises the issue of careful evaluation of the risks involved balanced against the expected benefits. The present review will evaluate, through the literature, the long-term side effects of immunosuppressive drugs commonly used in clinical practice, including cyclophosphamide, azathioprine, and, more recently, cyclosporine A, which has increased the spectrum of allograft transplants, in particular, cardiac and hepatic. Other immunosuppressive drugs have been used less extensively. Their side effects are less well known or are analogous to those of the conventional immunosuppressive drugs just mentioned, in particular, chlorambucil, whose mode of action follows a pathway similar to that of cyclophosphamide. New developments in the spectrum of immunosuppressive drugs in clinical practice, such as those of monoclonal antibodies, await future evaluation. Their use is only recent, and a discussion of their side effects is beyond the scope of this review.