One of the major goals in therapeutic immunosuppression has been to achieve long-term benefit from short-term therapy. The discovery in the mild-1980s that CD4 antibodies can induce immunological tolerance without depleting CD4+ T cells has reawakened interest in the use of nondepleting monoclonal antibodies for reprogramming the immune system in autoimmunity and in transplantation. Since that time, antibodies to CD11a, CD4OL, CD25, CD3, and CTLA4-Ig have all been shown capable of facilitating tolerance. In order to apply to principle of reprogramming in the clinic, we have sought to understand the mechanisms that are involved in its induction and its maintenance. In a number of allogeneic transplant models (heart, skin, bone marrow) anti-CD4 (+/- CD8) antibodies can be shown to block the rejection process while selectively promoting the development of CD4+ regulatory T cells responsible for a dominant tolerance that is reflected in findings of linked suppression and infectious tolerance. In these models, T cells that have never been exposed to CD4 antibodies become tolerant to grafted antigens by experiencing antigen in the microenvironment of regulatory T cells. Dominant tolerance is not the only mechanism that can be facilitated by CD4 Mab therapy. If allogeneic marrow is given at high cell doses under the umbrella of CD4 and CD8 antibodies, then tolerance can be achieved through clonal deletion. The mechanism by which regulatory CD4+ T cell suppress is not yet defined but could be active or passive. We have proposed the "civil service model" to explain how tolerant T cells might interfere with the responses of competent T cells in such a way as to render them tolerant.