Introduction: Stem cells are characterized by two fundamental properties; self-renewal and differentiation. Self-renewal is an integration of proliferation control with the maintenance of an undifferentiated state. Self-renewal trait is regulated by a dynamic process between transcription factors, epigenetic control, microRNA regulators, and cell-extrinsic signals from the niche of stem cells. The other feature of stem cells is the capability of differentiation to various cell types. Neural stem cells are able to differentiate to neuron, glial cell, and oligodendrocyte. The process of oligodendrocyte differentiation also is regulated by an interaction between the genetic and epigenetic programs. Recent studies reveal the key role of histone modifications in epigenetic regulation of gene expression during oligodendrocyte development. Moreover, retinoic acid pathway has been shown in stem cell differentiation toward neurons. Conclusion: Detection of signaling cascades and regulatory networks of self-renewal and differentiation of neural stem cells improve new therapeutic methods for neural diseases, such as brain injuries and brain tumors as well as neurodegenerative diseases, like Huntington, Alzheimer, Parkinson, and demyelination diseases, such as multiple sclerosis. Moreover, understanding of these pathways leads to specific and stable differentiation of neural stem cells toward functional oligodendrocyte for alternative therapy.