Multipotent neural stem cells (NSC) possess the ability to self-renew and to generate the three major central nervous system (CNS) cell types: neurons, astrocytes and oligodendrocytes. However, the molecular mechanisms that control NSC fate specification are not yet fully understood. Recent studies have provided evidence that soluble protein mediators such as cytokines and transcriptional factors play critical roles in cell fate determination. Furthermore, it has become apparent that epigenetic gene regulation plays an important intracellular role as cell-intrinsic programs in the specification of cell lineages. In this review, we focus on recent progress that addresses the mechanisms of NSC fate specification and their possible contribution in the field of regenerative medicine.