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The study of neuronal differentiation of embryonic stem cells has raised major interest over recent years. It allows a better understanding of fundamental aspects of neurogenesis and, at the same time, the generation of neurons as tools for various applications ranging from drug testing to cell therapy and regenerative medicine. Since the first report of human embryonic stem (ES) cells derivation, many studies have shown the possibility of directing their differentiation towards neurons. However, there are still many challenges ahead, including gaining a better understanding of the mechanisms involved and developing techniques to allow the generation of homogeneous neuronal and glial subtypes. We review the current state of knowledge of embryonic neurogenesis which has been acquired from animal models and discuss its translation intoin vitrostrategies of neuronal differentiation of ES cells. We also highlight several aspects of current protocols which need to be optimized to generate high-quality embryonic stem cell-derived neuronal precursors suitable for clinical applications. Finally, we discuss the potential of embryonic stem cell-derived neurons for cell replacement therapy in several central nervous system diseases. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.