This study investigates the mechanism of cisplatin resistance in cancers with *BRCA2* mutations. The authors found that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in *BRCA2* that restore the wild-type *BRCA2* reading frame. They demonstrated this in a cisplatin-resistant *BRCA2*-mutated breast cancer cell line, HCC1428, and a *BRCA2*-mutated pancreatic cancer cell line, Capan-1. In HCC1428, a secondary genetic change in *BRCA2* rescued *BRCA2* function, making the cells resistant to cisplatin. In Capan-1, cisplatin selection led to five different secondary mutations that restored the wild-type *BRCA2* reading frame, and these clones were resistant to both cisplatin and a poly(ADP-ribose) polymerase (PARP) inhibitor. The authors also evaluated recurrent cancers from patients with primary *BRCA2*-mutated ovarian carcinomas treated with cisplatin and found that the recurrent tumor that acquired cisplatin resistance had undergone reversion of its *BRCA2* mutation. These findings suggest that secondary mutations restoring the wild-type *BRCA2* reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy.This study investigates the mechanism of cisplatin resistance in cancers with *BRCA2* mutations. The authors found that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in *BRCA2* that restore the wild-type *BRCA2* reading frame. They demonstrated this in a cisplatin-resistant *BRCA2*-mutated breast cancer cell line, HCC1428, and a *BRCA2*-mutated pancreatic cancer cell line, Capan-1. In HCC1428, a secondary genetic change in *BRCA2* rescued *BRCA2* function, making the cells resistant to cisplatin. In Capan-1, cisplatin selection led to five different secondary mutations that restored the wild-type *BRCA2* reading frame, and these clones were resistant to both cisplatin and a poly(ADP-ribose) polymerase (PARP) inhibitor. The authors also evaluated recurrent cancers from patients with primary *BRCA2*-mutated ovarian carcinomas treated with cisplatin and found that the recurrent tumor that acquired cisplatin resistance had undergone reversion of its *BRCA2* mutation. These findings suggest that secondary mutations restoring the wild-type *BRCA2* reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy.