The gastrointestinal tract forms the largest surface in our body with constantly being exposed to various antigens, which provides unique microenvironment for the immune system in the intestine. Accordingly, the gut epithelium harbors the most T lymphocytes in the body as intraepithelial lymphocytes (IELs), which are phenotypically and functionally heterogeneous populations, distinct from the conventional mature T cells in the periphery. IELs arise either from pre-committed thymic precursors (natural IELs) or from conventional CD4 or CD8αβ T cells in response to peripheral antigens (induced IELs), both of which commonly express CD8α homodimers (CD8αα). Although lineage commitment to either conventional CD4 T helper (Th) or cytotoxic CD8αβ T cells as well as their respective co-receptor expression are mutually exclusive and irreversible process, CD4 T cells can be redirected to the CD8 IELs with high cytolytic activity upon migration to the gut epithelium. Recent reports show that master transcription factors for CD4 and CD8 T cells, ThPOK (Th-inducing BTB/ POZ-Kruppel-like factor) and Runx3 (Runt related transcription factor 3), respectively, are the key regulators for re-programming of CD4 T cells to CD8 lineage in the intestinal epithelium. This review will focus on the unique differentiation process of IELs, particularly lineage re-commitment of CD4 IELs.