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Summary THAP1 (THAP [Thanatos-associated protein] domain-containing, apoptosis-associated protein 1) is a ubiquitously expressed member of a family of transcription factors with highly conserved DNA-binding and protein-interacting regions. Mutations in THAP1 cause dystonia, DYT6, a neurologic movement disorder. THAP1 downstream targets and the mechanism via which it causes dystonia are largely unknown. Here, we show that wild-type THAP1 regulates embryonic stem cell (ESC) potential, survival, and proliferation. Our findings identify THAP1 as an essential factor underlying mouse ESC survival and to some extent, differentiation, particularly neuroectodermal. Loss of THAP1 or replacement with a disease-causing mutation results in an enhanced rate of cell death, prolongs Nanog, Prdm14, and/or Rex1 expression upon differentiation, and results in failure to upregulate ectodermal genes. ChIP-Seq reveals that these activities are likely due in part to indirect regulation of gene expression., Highlights • Wild-type THAP1 regulates ESC potential, survival, and proliferation • THAP1 is essential for ESC differentiation, particularly neuroectodermal • Thap1C54Y or ΔExon2 ESCs prolong expression of pluripotent genes upon differentiation • Thap1C54Y or ΔExon2 EBs show increased cell death and abnormal differentiation, Ehrlich and colleagues identified THAP1, mutations of which cause dystonia (DYT6), as an essential regulator of ESC survival, proliferation, and differentiation. As THAP1 mutations result in a neurologic disease, this work examined the effects of a causative mutation, C54Y, and an essentially null allele, ΔExon2, on neuronal differentiation.