We recently demonstrated that differentiation of cytotoxic T cells requires cooperation between T-cell receptor (TCR)/costimulation and γc-cytokines. Here we demonstrate that the transcription factor IFN regulatory factor 8 (IRF8) is expressed in CD8 T cells by the combination of these two signals. More importantly, depletion of IRF8 in these cells abrogated the differentiation of naive CD8 T cells into effector cells in an experimental graft-vs.-host disease mouse model. We also show that IRF8 seems to not operate upstream of other critical factors such as T-bet and eomesodermin, which have been implicated in effector maturation. Collectively, our work shows that IRF8 integrates the TCR/costimulation and γc-cytokine–signaling pathways and mediates the transition of naive CD8 T cells to effector cells, thus identifying IRF8 as one of the molecular regulators of CD8 T-cell differentiation.