Exhausted CD8(+) T (T-ex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T-eff) or memory (T-mem) CD8(+) T cells. T-ex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T-ex cells are a distinct immune subset, with a unique chromatin landscape compared with T-eff and T-mem cells. However, the mechanisms that govern the transcriptional and epigenetic development of T-ex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of T-ex cells in mice. TOX is largely dispensable for the formation of T-eff and T-mem cells, but it is critical for exhaustion: in the absence of TOX, T-ex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in T-ex cells. Robust expression of TOX therefore results in commitment to T-ex cells by translating persistent stimulation into a distinct T-ex cell transcriptional and epigenetic developmental program.