The considerable breadth of the self-directed T cell repertoire has only fully been appreciated during this past decade. It is a potential repertoire which can be tapped in various ways, most evidently in the study of autoimmune diseases, when because of a variety of factors, there is enhanced processing and presentation of determinants on self antigens. In this review, we have focused on the engagement of this self-reactive repertoire and some of the rules involved, which are not always so obvious. The total" residual" self-reactive repertoire directed against a single antigen (that remains after negative selection) will be a heterogeneous assemblage of T cells-(a) high affinity T cells directed against determinants whose presentation during tolerance induction was prevented, eg. through competitive binding by neighboring determinants;(b) lower affinity T cells directed against well-presented (dominant), as well as poorly-presented (cryptic) determinants; and (c) high affinity T cells directed against poorly-presented determinants, which are only presented during inflammation. Under conditions that favor upregulation of previously cryptic self determinants, one or more of the above subsets of the'protected'T cell repertoires can be stimulated by these self determinants, leading to induction of autoreactivity. The latter could eventually result in autoimmunity under permissive conditions governed by MHC and non-MHC genes. Interestingly, the very same repertoires that appear to be recruited into pathogenic autoimmune destruction may be alternatively manipulated as a source of anti-cancer treatment. It is now evident that many tumor antigens are unmutated self antigens, and cryptic determinants within such tumor antigens could be used to recruit the anticryptic T cell repertoire for induction of anti-tumor immunity.