DNA damage is a major risk factor for the decline of neuronal functions with age and in neurodegenerative diseases. While how DNA damage causes neurodegeneration is still being investigated, innovations over the past decade have provided significant insights into this issue. Breakthroughs in next-generation sequencing methods have begun to reveal the characteristics of neuronal DNA damage hotspots and the causes of DNA damage. Chromosome conformation capture-based approaches have shown that, while DNA damage and the ensuing cellular response alter chromatin topology, chromatin organization at damage sites also affects DNA repair outcomes in neurons. Additionally, neuronal activity results in the formation of programmed DNA breaks, which could burden DNA repair mechanisms and promote neuronal dysfunction. Finally, emerging evidence implicates DNA damage-induced inflammation as an important contributor to the age-related decline in neuronal functions. Together, these discoveries have ushered in a new understanding of the significance of genome maintenance for neuronal function.