Cell diversity in the central nervous system (CNS) is achieved by a highly regulated process of differentiation from multipotential neural stem cells. The spatial specificity and timing control of neural differentiation is achieved by the interplay between various genetic and epigenetic regulators. Oligodendrocytes, the myelinating cell in the CNS, play an important role in brain development and neuronal function. At present, multiple signaling pathways have been implicated in regulating in oligodendrocyte differentiation, however, the integration of these pathways with transcriptional and posttranscriptional regulatory networks are not fully understood. This review will focus on exploiting epigenetic mechanisms underlying oligodendrocyte development including chromatin remodeling by histone deacetylases and gene silencing by non-coding RNAs (e.g., microRNA), and attempts to summarize the recent advance as to the genetic and epigenetic interaction in controlling oligodendroglial differentiation and myelination.