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Two decades ago, two papers in Nature described how PARP inhibitors selectively killed cells deficient in the BRCA1 or BRCA2 tumour suppressor genes, observations that led to the first clinically approved treatment of a cancer with a targeted therapy selected based on a germline biomarker. This work was recognized by Nature as one of the top 20 discoveries in cancer in the twenty-first century and provides a compelling example of leveraging fundamental biology discovery for patient benefit. For people with specific forms of breast, ovarian, prostate or pancreatic cancer, these discoveries changed their care, enabling the use of more effective and better tolerated targeted therapies that both improve survival and quality of life. This in turn extended the role of germline BRCA1 and BRCA2 mutation testing from determining risk in the unaffected, to being a companion diagnostic biomarker used to determine therapy for a patient with cancer. The significance of these discoveries spread beyond BRCA1-mutant and BRCA2-mutant cancers: the synthetic lethal concept of the BRCA-PARP inhibitor effect highlighted the myriad levels of functional redundancy that exist in tumour cells and stimulated the search for other tumour-specific synthetic lethal effects that could be exploited therapeutically. Here we distill the learnings from the past two decades in this field.