BRCAness has become a term used to describe the consequences of loss of function of the BRCA1 and BRCA2 genes and some of their key functional partners in the DNA damage response, homologous recombination (HR) DNA repair, and DNA replication fork protection. This loss of function induces not only vulnerability to synthetic lethal strategies like PARP protein catalytic function inhibition and trapping, but also upregulation of alternative repair generating genome instability that goes beyond the induction of mutation necessary for oncogenesis and creates mutational signatures that allow identification tumour that bear the loss. In my lecture I will describe the latest results of clinical trials that target germline mutation driven BRCAness in both advanced and early forms of breast cancer. I will also describe our understanding of mechanisms by which these approaches fail, and how these resistance mechanisms and persisting vulnerabilities might be detected, understood and therapeutically targeted. I will describe strategies our group are using that combine both “forward translation” approaches using genetic perturbation screens in isogenic systems and “reverse translation” approaches that use the longitudinal analysis of the patient samples along their treatment journey. I will go onto describe the evidence that BRCAness can be induced by epigenetic mechanisms in cancer and focus on that evidence in breast cancer specifically. I will describe some of the BRCAness biomarker approaches that go beyond the detection of loss of function mutation in HR genes can capture these epigenetically driven HR deficient breast cancers, and both the advantages and the caveats to their use.