Genomic instability is a key driving force for the development and progression of many neurodegenerative diseases and central nervous system (CNS) cancers. The initiation of DNA damage responses (DDRs) is a critical step in maintaining genomic integrity and preventing such diseases. However, the absence of these responses or their inability to repair genomic or mitochondrial DNA damage resulting from insults, including ionizing radiation or oxidative stress, can lead to an accumulation of self-DNA in the cytoplasm. Resident CNS cells, such as astrocytes and microglia, are known to produce critical immune mediators following CNS infection due to the recognition of pathogen and damage-associated molecular patterns by specialized pattern recognition receptors (PRRs). Recently, multiple intracellular PRRs, including cyclic GMP-AMP synthase (cGAS), interferon gamma-inducible 16 (IFI16), absent in melanoma 2 (AIM2), and Z-DNA binding protein 1 (ZBP1), have been identified as cytosolic DNA sensors and play critical roles in glial immune responses to infectious agents. Intriguingly, some nucleic acid sensors have recently been shown to recognize endogenous DNA resulting from DNA damage and subsequently trigger immune responses in peripheral cell types, however, in the CNS, our understanding of these responses are limited. In this dissertation, we describe the functionality of the DNA sensors ZBP1, with regards to herpes simplex virus type-1 (HSV-1) infection in murine astrocytes and microglia, and cGAS with regards to DNA damage in human microglia.iv Our laboratory has previously reported that ZBP1 contributes to neurotoxic immune responses to HSV-1 infection, however, the exact mechanisms behind such responses were unknown. Here, we demonstrate that ZBP1 acts as a restriction factor for HSV-1 in murine astrocytes and microglia, and that it does so via the induction of necroptotic and apoptotic cell death pathways. While it remains to be seen whether ZBP1-mediated activation of cell death in glia contributes significantly to host protection or, rather, exacerbates HSV-1 encephalitis pathology, the identification of such a role in resident CNS cells may represent a novel target for therapeutic intervention to reduce HSV encephalitis-associated morbidity and mortality. Additionally, we report that cGAS serves as a mediator of proinflammatory immune responses following DNA damage in human microglia. We show that exposure to genotoxic insults such as ionizing radiation (IR) and hydrogen peroxide (H2O2) exposure not only elicit DNA damage, but also elicit production and secretion of proinflammatory cytokines in this glia. Furthermore, we show that cGAS deficiency results in markedly reduced levels of these cytokines following similar exposures. Surprisingly, we found that while cGAS deficient cells released lower levels of proinflammatory cytokines, they simultaneously expressed higher levels of DNA damage. Together, these data indicate a role for cGAS as a mediator of potentially neurotoxic inflammation following DNA damage. The mechanisms by which these responses occur require further study, as it is still unclear whether they are beneficial or detrimental. However, they may be targetable to augment glial responses that protect against tumorigenesis, or prevent responses that could initiate or exacerbate damaging neuroinflammation.