Immune regulatory interactions have been largely attributed to antagonistic T helper cell subsets whose cytokines are mutually inhibitory (Th1 vs. Th2). Here we emphasize two additional levels of regulation: the first involves the recognition of portions of antigen receptors of effector T cells, resulting in the induction of both CD4 and CD8 regulatory populations, capable of diminishing the responses by the pathogenic effector itself. The second includes a collection of cell populations found constitutively in all individuals whose specificity for antigen, if any, is being currently investigated. These two additional types of interaction involve cells belonging to a functional regulatory subset and include contributions from both innate and adaptive mechanisms of immune regulation. The answers to many quandaries in autoimmune disease may be sought by seeking to engage these lesser-understood regulatory populations.