Anti-CD4 monoclonal antibody (mAb) has been used extensively in transplant animal models. Adjunctive peri-operative administration of anti-CD4 mAb, in combination with other modalities, was able to induce donor-specific tolerance in the vast majority of recipients who had undergone grafting. The putative tolerogenic mechanisms are complex, and involve both central and peripheral immune regulatory pathways.In vitrotreatment of T cells with nondepleting anti-CD4 mAbs resulted, upon restimulation, in either CD4+ T-cell anergy or T-helper 2–type immune deviation. Studies of signal transduction pathways of T-cell activation illustrate the coreceptor function of CD4 molecules and provide the biochemical basis of the functional consequences of the CD4 blockade. Lymphocytes from anti-CD4–treated animals or lymphocytes culturedin vitroexhibited some common characteristics. In addition, researchers have been particularly interested in detecting an operational, infectious tolerance mechanism regulated by regulatory CD4+ T cellsin vivo. The improved understanding of this type of tolerance and the role of regulatory CD4+ T cells should lead to the development of novel therapeutic strategies, based on new concepts of immunosuppression in transplant recipients.