The recent years have been characterized by a surge of studies on the role of transcription factors and histone modifications in regulating the progression of progenitors into oligodendrocytes. This review summarizes this body of evidence and presents an integrated view of transcriptional networks and epigenetic regulators defining proliferating progenitors and their differentiation along the oligodendrocyte lineage. We suggest that transcription factors in proliferating progenitors have direct access to DNA, due to predominantly euchromatic nuclei. As progenitors differentiate, however, transcriptional competence is modulated by the formation of heterochromatin, which modifies the association of DNA with nucleosomal histones and renders the access of transcription factors dependent on the activity of epigenetic modulators. These concepts are delineated within the context of development, and the potential functional implications are discussed.