Genome stability is maintained by a number of elegant mechanisms, which sense and repair damaged DNA. Germline defects that compromise genomic integrity result in cancer predisposition, exemplifed by rare syndromes caused by mutations in certain DNA repair genes. These individuals often exhibit other symptoms including progeria and neurodegeneration. Paradoxically, some of these deleterious genetic alterations provide novel therapeutic opportunities to target cancer cells; an excellent example of such an approach being the recent development of poly (ADP-ribose) polymerase inhibitors as the frst ‘synthetic lethal’ medicine for patients with BRCA-mutant cancers. The therapeutic exploitation of synthetic lethal interactions has enabled a novel approach to personalised medicine based on continued molecular profling of patient and tumour material. This profling may also aid clinicians in the identifcation of specifc drug resistance mechanisms following relapse, and enable appropriate modifcation of the therapeutic regimen. This chapter focuses on therapeutic strategies designed to target aspects of the DNA damage response, and examines emerging themes demonstrating mechanistic overlap between DNA repair and neurodegeneration.