Neurodegenerative disorders are primarily characterized by neuron loss progressively leading to cognitive decline and the manifestation of incurable and debilitating conditions, such as Alzheimer's, Parkinson's, and Huntington's diseases. Loss of genome maintenance causally contributes to age-related neurodegeneration, as exemplified by the premature appearance of neurodegenerative features in a growing family of human syndromes and mice harbouring inborn defects in DNA repair. Here, we discuss the relevance of persistent DNA damage, key DNA repair mechanisms and compromised genome integrity in age-related neurodegeneration highlighting the significance of investigating these connections to pave the way for the development of rationalized intervention strategies aimed at delaying the onset of neurodegenerative disorders and promoting healthy aging.