Written and edited by experts in the field, this collection from Cold Spring Harbor Perspectives in Biology reviews how self-tolerant T- and B-cell populations are produced. The contributors discuss the elimination of autoreactive lymphocytes during their development in the thymus and bone marrow, the suppression of autoreactive cells by regulatory T cells in the periphery, and intrinsic mechanisms that produce clonal anergy. The roles of dendritic cells in antigen presentation and mechanisms that prevent autoreactivity in natural killer cells are also covered.