Neurological syndromes, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis, and lysosomal storage disorders, such as Battens disease, are devastating because they result in increasing loss of cognitive and physical function. Sadly, no drugs are currently available to halt their progression. The relative paucity of curative approaches for these and other conditions of the nervous system have led to a widespread evaluation of alternative treatment modalities including cell-based interventions. Several cell types have been tested successfully in animal models where safety and efficacy have been demonstrated. Early clinical trials have also been initiated in humans, and some have shown a degree of success albeit on a more limited scale than in animal experiments. Recent demonstrations that pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, can differentiate into a variety of specific neural phenotypes has stimulated worldwide enthusiasm for developing cell-based intervention of neurological disease. Indeed, several groups are preparing investigational new drug applications to treat disorders as diverse as macular degeneration, lysosomal storage diseases, and Parkinson's disease. It is noteworthy that cell replacement therapies for neurological conditions face key challenges, some of which are unique, because of the development and organization of the nervous system, its metabolism, and connectivity. Choice of the cell (or cells), the process of manufacturing them, defining the delivery pathway, developing and testing in an appropriate preclinical model, selecting a patient population, and visualizing and following or monitoring patients all pose specific issues as related to the central and peripheral nervous systems. In this review, we address a myriad of challenges that are solvable, but require careful planning and attention to the special demands of the human nervous system.