Defects in the response to DNA single-strand or double-strand breaks underpin many human diseases associated with disorders of the nervous system. During nervous system development endogenous DNA damage often results in apoptosis, although cell replacement can occur from germinal zones within this rapidly proliferating tissue. However, if this damage surveillance is faulty, cells with genomic damage may inappropriately become incorporated into the nervous system, and the subsequent demise of these cells may result in neurodegeneration. Ataxia telangiectasia results from defective DNA double strand break signaling, and during development a failure to eliminate damaged neural precursor cells may cause the neurodegeneration present in this disease. In contrast, postmitotic neurons in the mature brain are faced with a less facile option, and in this situation DNA breaks may interfere with transcription required for cellular survival. This scenario may reflect neurodegeneration that occurs in spinocerebellar ataxia with axonal neuropathy, in which single strand break repair is defective. Therefore, the response to DNA damage in the nervous system occurs in a distinct spatiotemporal manner utilizing different DNA repair pathways to ensure genomic stability and to prevent disease.