T-bet is a member of the T-box family of transcription factors that appears to regulate lineage commitment in CD4 T helper (TH) lymphocytes in part by activating the hallmark TH1 cytokine, interferon-γ (IFN-γ). IFN-γ is also produced by natural killer (NK) cells and most prominently by CD8 cytotoxic T cells, and is vital for the control of microbial pathogens. Although T-bet is expressed in all these cell types, it is required for control of IFN-γ production in CD4 and NK cells, but not in CD8 cells. This difference is also apparent in the function of these cell subsets. Thus, the regulation of a single cytokine, IFN-γ is controlled by distinct transcriptional mechanisms within the T cell lineage.