Immunity to intracellular pathogens requires dynamic balance between terminal differentiation of short-lived, cytotoxic effector CD8 super(+) T cells and self-renewal of central-memory CD8 super(+) T cells. We now show that T-bet represses transcription of IL-7R alpha and drives differentiation of effector and effector-memory CD8 super(+) T cells at the expense of central-memory cells. We also found T-bet to be overexpressed in CD8 super(+) T cells that differentiated in the absence of CD4 super(+) T cell help, a condition that is associated with defective central-memory formation. Finally, deletion of T-bet corrected the abnormal phenotypic and functional properties of "unhelped" memory CD8 super(+) T cells. T-bet, thus, appears to function as a molecular switch between central- and effector-memory cell differentiation. Antagonism of T-bet may, therefore, represent a novel strategy to offset dysfunctional programming of memory CD8 super(+) T cells.