DNA repair has been shown to affect the cellular response to platinum-based therapy in a variety of cancers; however, translating this knowledge to the clinic has proven difficult and yielded mixed results. In this issue of Cancer Discovery, Van Allen and colleagues have analyzed responders and nonresponders to neoadjuvant platinum-based therapy with locally advanced urothelial cancer and identified a series of mutations in the nucleotide excision repair (NER) gene ERCC2 that correlate with the response to platinum-based therapy. This work provides evidence that defects in NER can be exploited to maximize the efficacy of conventional platinum-based chemotherapy.