Given that neurologic dysfunction in CNS disorders is usually due to cell loss, the primary goal of NSC therapy is to replace missing cells and tissue. A fundamental precondition for a cell replacement approach is the generation of specialized cells specific for each neurologic disease. The first indication that brain cells could be replaced came from work in animal models of PD.2Experimental data from rodents and nonhuman primates demonstrated that dopaminergic neurons derived from fetal ventral mesencephalon formed synaptic contacts, released dopamine, and ameliorated PD-like symptoms when grafted intrastriatally. Clinical trials of human fetal mesencephalic tissue transplantation in patients with PD were started in 1987 and showed improvement in some patients.3These early studies raised many questions regarding the optimal site of grafting, dose of cell delivery, graft rejection, and adverse effects. Moreover, it became clear that fetal mesencephalic tissue, requiring up to 4 fetuses per patient, was not a practical source of transplantable dopamine neurons. Nevertheless, these studies provided proof of principle for cell replacement in PD and boosted the search for an ethically acceptable and inexhaustible source of dopamine neurons. There are no established methods by which specific neuronal types can be selectively enriched from adult NSCs. As an alternative, it has been suggested that stem cells from nonneural tissue could transdifferentiate into neural progeny.4Although it is clear that bone marrow stromal cells can acquire neural markers,5it remains controversial whether they are capable of acquiring the full range of neuronal functions. To date, the best candidate for mass generation of specialized neural cells is the embryonic stem cell (ESC). By recapitulation of developmental conditions in culture, it is possible to grow mouse and human ESCs and to generate cultures enriched with dopaminergic cells, motor neurons, oligodendrocytes, and retinal cells, among others.6Moreover, mouse ESC–derived motor neurons can establish functional synapses with muscle fibers in vitro and extend axons to ventral roots after transplantation into motoneuron-injured adult rats.7Although protocols for generation of dopaminergic neurons from human ESCs in vitro are available,8their grafting in experimental animals has been hampered by poor survival of the transplanted cells, which is a major obstacle in the application of cell therapy for PD.