The development of the human central nervous system is a complex process involving highly coordinated periods of neuronal proliferation, migration and differentiation. Disruptions in these neurodevelopmental processes can result in microcephaly, a neuropathological disorder characterized by a reduction in skull circumference and total brain volume, whereas a failure to maintain neuronal health in the adult brain can lead to progressive neurodegeneration. Defects in the cellular pathways that detect and repair DNA damage are a common cause of both these neuropathologies and are associated with a growing number of hereditary human disorders. In particular, defects in the repair of DNA single strand breaks, one of the most commonly occurring types of DNA lesion, have been associated with three neuropathological diseases: ataxia oculomotor apraxia 1, spinocerebellar ataxia with neuronal neuropathy 1 and microcephaly, early-onset, intractable seizures and developmental delay. A striking similarity between these three human diseases is that they are all caused by mutations in DNA end processing factors, suggesting that a particularly crucial stage of DNA single strand break repair is the repair of breaks with 'damaged' termini. Additionally all three disorders lack any extraneurological symptoms, such as immunodeficiency and cancer predisposition, which are typically found in other human diseases associated with defective DNA repair. However despite these similarities, two of these disorders present with progressive cerebellar degeneration, whereas the third presents with severe microcephaly. This review discusses the molecular defects behind these disorders and presents several hypotheses based on current literature on a number of important questions, in particular, how do mutations in different end processing factors within the same DNA repair pathway lead to such different neuropathologies?.