The DNA damage response (DDR) is a key factor in the maintenance of genome stability. As such, it is a central axis in sustaining cellular homeostasis in a variety of contexts: development, growth, differentiation, and maintenance of the normal life cycle of the cell. It is now clear that diverse mechanisms encompassing cell cycle regulation, repair pathways, many aspects of cellular metabolism, and cell death are inter-linked and act in concert in response to DNA damage. Defects in the DDR in proliferating cells can lead to cancer, while DDR defects in neurons may result in neurodegeneration. Mature neurons are highly differentiated, post-mitotic cells that cannot be replenished after disease or trauma. Their high metabolic activity generates large amounts of reactive oxygen species with DNA damaging capacity. Moreover, their intense transcriptional activity increases the potential for genomic DNA damage. Respectively, neurons have elaborate mechanisms to defend the integrity of their genome, thus ensuring their longevity and functionality in the face of these threats. Over the course of the past two decades, there has been a substantial increase in our understanding of the role of glial cells in supporting the neuronal cell DDR and longevity. This review article focuses on the potential role of the DDR in the etiology and pathogenesis of neurodegenerative diseases, and in addition, it describes various aspects of glial cell functionality in two genomic instability disorders: ataxia telangiectasia (A-T) and Nijmegen breakage syndrome.