Abstract: Thymic epithelial and nurse cells from different species express a repertoire of neuroendocrine polypeptide precursors. This repertoire exerts a dual role in T-lymphocyte selection according to their status either as cryptocrine signals or as neuroendocrine self-antigens of the peptide sequences that are processed from those precursors then presented to pre-T cells. Thymic neuroendocrine self-antigens correspond to peptide sequences highly conserved throughout evolution of their family. Though thymic MHC class I molecules are involved in the processing of thymic neuroendocrine self-antigens, preliminary data show that their presentation to pre-T cells is not allelically restricted. Thymic T-cell education in neuroendocrine families also implies that the structure of a given family may be presented to pre-T cells. Our studies have evidenced the homology between thymic neuroendocrine-related self-antigens and dominant T-cell epitopes of peripheral neuroendocrine signals (neuroendocrine autoantigens). The biochemical difference between neuroendocrine autoantigens and homologous thymic self-antigens might explain the opposite immune responses evoked by those two types of antigens (activation and memory induction vs. tolerogenic effect). Altogether, these studies support the therapeutic use of thymic neuroendocrine self-antigens in reprogramming the immunological self-tolerance that is broken in autoimmune endocrine diseases like insulin-dependent diabetes type I. As recently stated by P. M. Allen in an important review, the fate of developing T lymphocytes in the thymus is influenced by the numerous types of peptidic interactions within the thymic cellular environment. 1 To define the precise nature of thymic cells and naturally occurring biochemical peptide signals involved in positive and negative selection of immature T cells has become a prominent objective for the future research efforts in thymic physiology. This paper will try to show how thymic neuroendocrine-related peptides synthesized and processed within the thymic microenvironment indeed can play a role both in the development of the peripheral T-cell repertoire and in the death of randomly rearranged, self-reactive T cells.