Monoclonal antibodies are homogeneous sets of immunoglobulins with well-defined specificity and biochemical characteristics. They were introduced into clinical practice in the early 1980s, and since then their use has rapidly expanded. Most of the side effects observed with first-generation murine (mouse or rat) antibodies have been successfully overcome with the advent of humanized (chimeric or CDR-grafted) and more recently fully human antibodies. Our aim is to review the major steps in the development of therapeutic monoclonal antibodies in the fields of transplantation and autoimmunity, and discuss the salient features of antibodies presently used in the clinic-notably anti-T-cell and anticytokine antibodies. The discussion will also focus on the unique capacity of some monoclonal antibodies to induce immune tolerance.