The increasing acceptance of the notion that autospecific B lymphocytes are inactivated, either by clonal deletion or anergy (reviewed by Nossal'), now permits a new look into some of the implications of self-tolerance. In this review we discuss the implications of a newly discovered form of B-cell tolerance and speculate on the possibility that an immune system that generates in its primary repertoire a very high proportion of self-reactive B cells may in fact be pursuing the most efficient strategy for building a repertoire capable of optimally recognizing non-self. Our recent work with transgenic mice2 along with the results of Weigert's gr~ up~-~ has indicated a novel mechanism of B-cell tolerance called receptor editing. This mechanism involves secondary (nested) immunoglobulin light chain gene rearrangement in immature, bone marrow B cells whose receptors are crosslinked by autoantigen. Such rearrangements are mediated by ongoing or newly induced recombinase activity, which allows the cell to change its specificity and effectively results in deletion of the autoreactive receptor while retaining the cell that originally expressed it. These conclusions are based on the observed increase in recombination activator gene (RAG) expression and endogenous light chain gene rearrangement and expression in cells that should otherwise be constrained from further rearrangement by the mechanisms of allelic exclusion. Although the validity of the receptor-editing model has yet to be proved in a nontransgenic system, information from a number of sources suggests, albeit indirectly, that it may well be operative in normal cell^.^-^ Why should one need the efficiency afforded by receptor editing? There is already massive waste in B-cell development, both at early stages of development in the bone marrowlo and later, after potentially responsive B-cells have been generated and exported to the periphery." One possible explanation is that self reactivity is actually far more likely than commonly thought, that is, that a far higher proportion of self-reactive I3 cells is generated in the repertoire than one