TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Exhausted CD8+ T cells (T_EX) in chronic infections and cancer exhibit limited effector function, high inhibitory receptor co-expression, and extensive transcriptional changes compared to effector (T_EFF) or memory (T_MEM) CD8+ T cells. T_EX are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T_EX are a distinct immune subset with a unique chromatin landscape compared to T_EFF and T_MEM. However, the mechanisms governing the transcriptional and epigenetic development of T_EX remain unknown. The study identifies the HMG-box transcription factor TOX as a central regulator of T_EX. TOX is largely dispensable for T_EFF and T_MEM formation, but is critical for exhaustion. TOX is induced by calcineurin and NFAT2 and operates in a feed-forward loop to become calcineurin independent and sustained in T_EX. Thus, robust TOX expression results in commitment to T_EX by translating persistent stimulation into a distinct T_EX transcriptional and epigenetic developmental program. Following activation by antigen, naïve CD8+ T cells undergo extensive molecular rewiring into effector CD8+ T cells. If antigen is cleared, a subset of T_EFF persist, forming long-lived, self-renewing memory T cells capable of mounting rapid recall responses. In contrast, during chronic infections or cancer, this differentiation is diverted and T cells can instead become exhausted. Exhausted CD8+ T cells may balance partial pathogen or tumor control while restraining immunopathology. However, the consequence of restrained functionality is disease persistence and/or progression. T cell exhaustion is a common feature of many chronic infections and cancers in mice and humans. Indeed, T_EX are a major target of checkpoint blockade in patients with cancer. T_EX are characterized by the hierarchical loss of cytokine production, high inhibitory receptor co-expression, altered metabolism, and impaired proliferative potential and survival. T_EX also display a distinct transcriptional program highlighted by altered use of key transcription factors. Moreover, recent epigenetic analysis revealed that T_EX differ from T_EFF and T_MEM by ~6000 open chromatin regions, similar to differences between other major hematopoietic lineages. Thus, T_EX are not simply a state of activation of T_EFF or T_MEM, but rather a distinct cell type. Yet, the mechanisms that initiate this T_EX fate commitment and epigenetic and transcriptional programming have remained elusive. Here, we identify a requisite role for the HMG-box TF TOX in programming the early epigenetic events driving fate commitment of T_EX. While robustly expressed in T_EX, TOX is only transiently expressed at low levels during acute infections. Moreover, T_EFF and T_MEM can form without TOX whereas T_EX cannot. TOX isTOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Exhausted CD8+ T cells (T_EX) in chronic infections and cancer exhibit limited effector function, high inhibitory receptor co-expression, and extensive transcriptional changes compared to effector (T_EFF) or memory (T_MEM) CD8+ T cells. T_EX are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T_EX are a distinct immune subset with a unique chromatin landscape compared to T_EFF and T_MEM. However, the mechanisms governing the transcriptional and epigenetic development of T_EX remain unknown. The study identifies the HMG-box transcription factor TOX as a central regulator of T_EX. TOX is largely dispensable for T_EFF and T_MEM formation, but is critical for exhaustion. TOX is induced by calcineurin and NFAT2 and operates in a feed-forward loop to become calcineurin independent and sustained in T_EX. Thus, robust TOX expression results in commitment to T_EX by translating persistent stimulation into a distinct T_EX transcriptional and epigenetic developmental program. Following activation by antigen, naïve CD8+ T cells undergo extensive molecular rewiring into effector CD8+ T cells. If antigen is cleared, a subset of T_EFF persist, forming long-lived, self-renewing memory T cells capable of mounting rapid recall responses. In contrast, during chronic infections or cancer, this differentiation is diverted and T cells can instead become exhausted. Exhausted CD8+ T cells may balance partial pathogen or tumor control while restraining immunopathology. However, the consequence of restrained functionality is disease persistence and/or progression. T cell exhaustion is a common feature of many chronic infections and cancers in mice and humans. Indeed, T_EX are a major target of checkpoint blockade in patients with cancer. T_EX are characterized by the hierarchical loss of cytokine production, high inhibitory receptor co-expression, altered metabolism, and impaired proliferative potential and survival. T_EX also display a distinct transcriptional program highlighted by altered use of key transcription factors. Moreover, recent epigenetic analysis revealed that T_EX differ from T_EFF and T_MEM by ~6000 open chromatin regions, similar to differences between other major hematopoietic lineages. Thus, T_EX are not simply a state of activation of T_EFF or T_MEM, but rather a distinct cell type. Yet, the mechanisms that initiate this T_EX fate commitment and epigenetic and transcriptional programming have remained elusive. Here, we identify a requisite role for the HMG-box TF TOX in programming the early epigenetic events driving fate commitment of T_EX. While robustly expressed in T_EX, TOX is only transiently expressed at low levels during acute infections. Moreover, T_EFF and T_MEM can form without TOX whereas T_EX cannot. TOX is