Differentiation of CD4(+)CD8(+) double-positive (DP) thymocytes into either CD4(+)-helper or CD8(+)-cytotoxic lineages involves several phases. It has been suggested that, following initial specification to one of the lineages by a set of lineage-specific genes during positive selection, stable cell identity is established during the commitment process by eliminating differentiation potential toward the other lineage. While the Runx3 transcription factor fixes the Cd4 gene into a silenced state during cytotoxic-lineage cell differentiation, the ThPOK transcription factor is both necessary and sufficient to generate a CD4(+)CD8(-) phenotype in post-selection thymocytes, regardless of the MHC specificity of the TCRs. Recent studies have revealed that a reciprocal antagonistic interplay between Runx3 and ThPOK is a central component in the transcription factor network governing the helper versus cytotoxic-lineage decision.