Significance Transplantation of human myelinogenic cells represents a realizable strategy for treatment of congenital and acquired demyelinating diseases. Although generation of undifferentiated neural stem and progenitors is feasible, the induction of myelinogenic cell fate remains a significant challenge. In this paper, we describe, to our knowledge, the first comprehensive study of transcription factor expression and function by purified neural and oligodendrocyte progenitors obtained directly from human brain tissue. We have identified those transcription factors capable of regulating oligodendrocyte progenitor fate and establish that among these, only SOX10 was capable of comprehensively inducing oligodendrocyte fate both in vitro and following transplantation into a model of human leukodystrophy. Thus, viral and pharmacologic approaches to increasing SOX10 expression likely will improve the outcome of human transplant therapy.