Because of their unique ability to self-renew and generate all cell lineages of an organism (pluripotency), embryonic stem cells represent a versatile model for developmental biology, and a promising avenue for regenerative medicine. Understanding the molecular mechanisms regulating self-renewal and pluripotency provides a productive path to effectively use embryonic stem cells, and to improve current methods for induction/differentiation of pluripotent stem cells and direct somatic cell reprogramming. This study provides novel insights into transcriptional regulation of the stem cell state by characterizing interactions between key transcription factors SOX2 and OCT4, and a recently identified, multifunctional, stem cell coactivator—the xeroderma pigmentosum, complementation group C DNA repair complex—to control pluripotency gene-expression networks.