The interplay of transcription and epigenetic marks is essential for oligodendrocyte progenitor cell (OPC) proliferation and differentiation during development. Here, we review the recent advances in this field and highlight mechanisms of transcriptional repression and activation involved in OPC proliferation, differentiation and plasticity. We also describe how dysregulation of these epigenetic events may affect demyelinating disorders, and consider potential ways to manipulate NG2 cell behavior through modulation of the epigenome.