During thymic development, thymocytes expressing a T cell receptor consisting of an alpha and beta chain (TCRαβ), commit to either the cytotoxic- or T helper-lineage fate. This lineage dichotomy is controlled by key transcription factors, including the T helper (Th) lineage master regulator, the Th-inducing BTB/POZ domain-containing Kruppel-like zinc-finger transcription factor, ThPOK, (formally cKrox or Zfp67; encoded by Zbtb7b), which suppresses the cytolytic program in major histocompatibility complex (MHC) class II-restricted CD4⁺ thymocytes and the Runt related transcription factor 3 (Runx3), which counteracts ThPOK in MHC class I restricted precursor cells and promotes the lineage commitment of CD8αβ⁺ cytolytic T lymphocytes (CTL). ThPOK continues to repress the CTL gene program in mature CD4⁺ T cells, even as they differentiate into effector Th cell subsets. The Th cell fate however is not fixed and two recent studies showed that mature, antigen-stimulated CD4⁺ T cells have the flexibility to terminate the expression of ThPOK and functionally reprogram to cytotoxic effector cells. This unexpected plasticity of CD4⁺ T cells results in the post-thymic termination of the Th lineage fate and the functional differentiation of distinct MHC class II-restricted CD4⁺ CTL. The recognition of CD4 CTL as a defined separate subset of effector cells and the identification of the mechanisms and factors that drive their reprogramming finally create new opportunities to explore the physiological relevance of these effector cells in vivo and to determine their pivotal roles in both, protective immunity as well as in immune-related pathology.