Elucidation of genetic and epigenetic mechanisms underlying neoplasia is one of the great success stories of modern science, but this success has not been associated with parallel improvements in the treatment of malignant tumors. One possible explanation for this failure is that the most important variables that support growth of malignancies are not yet identified. Another possible explanation, however, is that multiple variables important in neoplastic progression combine to create a level of disease complexity not taken into account by current therapeutic approaches. The study of development and neoplasia in the CNS provides some of the strongest support for the latter view--a view that, if correct, would suggest that a radical rethinking of the biology of malignancy is required if we are to make progress in the treatment of this important medical condition.