Tolerance must be maintained to prevent deleterious immune responses. Thus, when tolerance is lost, autoimmunity can result. A number of novel approaches to (re-) induce tolerance for potential clinical applications have been developed in the last decade. Our lab has implemented an immunoglobulin-based gene therapy approach, which may have powerful implications for the treatment of human conditions. These include a variety of autoimmune diseases, transplantation, and the immune response to therapeutic proteins (as in the treatment of hemophilia A) or gene therapy per se. We clone the target (immunogenic) protein in frame with an immunoglobulin heavy chain and deliver it via retrovirus to an activated B cell. In our system, we observe tolerance to multiple epitopes of the protein cloned. An important advantage of this regimen is that identification of the precise peptide epitopes of a target protein is not necessary since selection and presentation by the hosts own antigen presenting cells (APCs) eliminates the issue of HLA polymorphism. Additionally, our data indicate that these tolerogenic B cells are stimulating an endogenous population of regulatory T cells, which are effective at suppressing the immune response in both naïve and primed hosts. Thus, this approach has potential for future clinical therapy.