The processing and presentation of self-proteins is essential to develop an effective immune system, with almost all T cells only ever encountering self-peptide/MHC ligands. How positive selection in the thymus occurs with a weak interaction between the TCR and self-pMHC remains unresolved. The recent identification of a naturally occurring positive selecting self-peptide, gp250, for the MCC/I-Ek specific T cell, AND, has provided some key insights. Despite the weak 3D affinity of the positive selecting AND TCR:gp250/I-Ek interaction, it induces a sustained Ca2+ flux and Erk signaling. Transcriptional profiling revealed the unique expression of a voltage-gated sodium channel (VGSC) in DP thymocytes. Blocking of this channel with tetrodotoxin inhibited positive selection of AND and polyclonal CD4 T cells in vitro. VGSC sh-RNA knockdown inhibited the selection of CD4, but not CD8 T cells. Thus, the expression of a VGSC at the DP stage increases the sensitivity of signaling induced by positively selecting ligands, thereby, providing a mechanism by which a weak TCR:self-peptide interaction can result in a sustained developmental signal. One enigma regarding positive selection is that AND TCR recognizes gp250 self-peptide with a high degree of specificity, akin to what is seen with foreign antigen. The self-peptide repertoire is significantly smaller than the T cell repertoire, therefore, each self-peptide has to select many unrelated T cells. Other studies have shown that a single peptide/MHC can select a large number of T cells. To reconcile this dichotomy, we propose a model in which positive selection is not simply a live or die process, but that the strength of the interaction between a TCR and the positive selecting ligand is deterministic for the functional activity of the peripheral T cells.