Evidence suggests that the brain, like many other tissues, is in a state of dynamic equilibrium. It has an endogenous population of stem cells that proliferate in response to environmental and pharmacological manipulations and that can replace cells lost in some experimental lesions. However, the fact remains that neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are characterised by continuous loss of neurons that are not replaced. In this hypothesis, we postulate that a primary deficit in neural stem-cell proliferation; migration, or differentiation, or both, might contribute to net cell loss and neuronal circuit disruption in these disorders. Experimental validation of this hypothesis would not only substantially advance understanding of the pathogenesis of these diseases, but could also have profound implications for future treatment of these incurable disorders.