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ABSTRACT Introduction BRCA1 and BRCA2 (BRCA1/2) mutation breast cancers constitute an uncommon, but unique group of breast cancers that present at a younger age, and are underscored by genomic instability and accumulation of DNA damage. Talazoparib is a potent poly(ADP-ribose) polymerase (PARP) inhibitor that exploits impaired DNA damage response mechanisms in this population of patients and results in significant efficacy. Based on the results of the EMBRACA trial, talazoparib was approved for the treatment of patients with advanced germline BRCA1/2 mutant breast cancer. Areas covered In this review, the authors highlight the relevant clinical trials of talazoparib, as well as, safety, tolerability, and quality of life considerations. They also examine putative response and resistance mechanisms, and rational combinatorial therapeutic strategies under development. Expert opinion Talazoparib has been a major advance in the treatment of germline BRCA1/2 mutation breast cancer with both clinical efficacy and improvement in quality of life compared to standard cytotoxic chemotherapy. To date, the optimal sequencing of talazoparib administration in the metastatic setting has not yet been established. A deeper understanding of response and resistance mechanisms, and more broadly, the DNA repair pathway, will lead to additional opportunities in targeting this pathway and open up therapeutic indications to a broader patient population.