The traditional concepts of immunization are undergoing substantial revisions that are likely soon to result in new therapies for autoimmune diseases. Advances in the understanding of foreign/self distinction by the immune system have revealed that eradication of foreign antigens is not necessarily the sole objective of sensitized lymphocytes, and that immunological tolerance to self involves more than prenatal deletion of forbidden lymphocyte clones in the thymus. This article will review the immunological basis of oral antigen immunoregulatory therapy and will contrast it with a new antigen-specific immunostimulatory treatment of autoimmune diabetes in non-obese diabetic (NOD) mice. As is true for an antigen-sensitive state, the generation of antigenic unresponsiveness requires repeated and even persistent antigen presentation.’Often, the initial antigen exposure occurs in the thymus, but it can also occur in the peripheral immune systems2 Current debate is centered on the relative roles of clonal inactivation (anergy), clonal deletion, and active immunoregulation in the induction of extrathymic tolerance. The importance of anergy is supported by multiple in vivo investigations of transgenic3 or superantigen-treated4 mice and by in vitro studies in which antigen-induced proliferation of a