Introduction A loss of central nervous system (CNS) myelin is characteristic of several neurological pathologies and trauma that include multiple sclerosis (MS)[1–3], brain injury [4], spinal cord injury (SCI)[5], and stroke [6]. Myelin loss is also linked to psychiatric disorders such as schizophrenia [7], and is correlated with functional deterioration associated with aging [8, 9], and Alzheimer’s disease [10]. Together these disorders affect a patient population of approximately 10.3 million individuals in the United States. Although demyelination is concomitant with other disease processes in each of these disorders, it remains possible that remyelination can alleviate clinical deterioration by decreasing axonal degeneration and transection and associated functional deficits [11]. Indeed, remyelination has been shown to restore saltatory conduction in axons [12] and ameliorate locomotor deficits in animals [13]. Thus, it is relevant to consider the clinical application of myelinogenic treatments to foster remyelination. In experimental models of demyelination, endogenous [14] or transplanted [15] mature oligodendrocytes are incapable of remyelination. By contrast, current evidence suggests that cell replacement strategies using oligodendrocyte progenitor cells (OPCs), such as human embryonic stem cell (hESC)-derived OPCs, promote remyelination and improve locomotor outcomes in animals [16]. Although considerable progress has been made in recent years to demonstrate the effectiveness of cell-based remyelination treatments, several significant obstacles must be overcome before this research translates to the clinic. Particular to hESC-derived OPCs, these hurdles include determination of preclinical utility for etiologically disparate demyelinating conditions, mitigation of the risks of cell transplantation, large-scale manufacturing, and regulatory considerations for government approval. Here we present the emerging perspective that stem cell-mediated remyelination of the adult CNS is a viable therapeutic strategy with potential beyond remyelination and discuss the challenges to the development of such therapeutic applications.