The study identifies the HMG-box transcription factor TOX as a central regulator of exhausted CD8+ T cells (T_EX). TOX is essential for the development of T_EX but dispensable for effector (T_EFF) and memory (T_MEM) CD8+ T cells. TOX is induced by calcineurin and NFAT2 and operates in a feed-forward loop to become calcineurin-independent and sustained in T_EX. Robust TOX expression results in the commitment to T_EX by translating persistent stimulation into a distinct T_EX transcriptional and epigenetic developmental program. TOX represses terminal T_EFF-specific epigenetic events while initiating key T_EX-specific epigenetic changes, highlighting its role as a critical coordinator of T_EX programming. These findings have implications for the ontogeny of T_EX and therapeutic strategies targeting this cell type.The study identifies the HMG-box transcription factor TOX as a central regulator of exhausted CD8+ T cells (T_EX). TOX is essential for the development of T_EX but dispensable for effector (T_EFF) and memory (T_MEM) CD8+ T cells. TOX is induced by calcineurin and NFAT2 and operates in a feed-forward loop to become calcineurin-independent and sustained in T_EX. Robust TOX expression results in the commitment to T_EX by translating persistent stimulation into a distinct T_EX transcriptional and epigenetic developmental program. TOX represses terminal T_EFF-specific epigenetic events while initiating key T_EX-specific epigenetic changes, highlighting its role as a critical coordinator of T_EX programming. These findings have implications for the ontogeny of T_EX and therapeutic strategies targeting this cell type.