Naive CD8 T cells proliferate in response to TCR and CD28 signals, but require IL-12 or type I IFN to survive and develop optimal effector functions. Although murine CTL generated in vitro in response to IL-12 or IFN-α had comparable effector functions, IL-12-stimulated cells were significantly more effective in controlling tumor in an adoptive immunotherapy model. They maintained high numbers and function, whereas IFN-α-stimulated cells declined in number and became exhausted. Consistent with this, IFN-α-stimulated cells in the tumor expressed higher levels of programmed death 1 (PD-1) inhibitory receptor than did IL-12-stimulated cells. When blocking Ab specific for the PD-L1 ligand of PD-1 was administered, the efficacy of IFN-α-stimulated CTL became comparable with that of IL-12-stimulated cells. Thus, IL-12 and IFN-α differentially program CD8 T cells to re-express distinct levels of PD-1 upon re-encountering Ag, resulting in IL-12-stimulated cells being less susceptible to exhaustion in the face of sustained tumor Ag.