A multidisciplinary approach to breast cancer management is well established as the standard of care. However, questions remain about the optimal approach for the timing and application of systemic therapy and local therapy. The safety and efficacy of combined versus sequential systemic therapy and radiotherapy has been determined for some treatments in routine use, however for newer agents those issues have yet to be resolved. New systemic therapies are being used in both early stage and metastatic breast cancer, with the potential for synergistic toxicities or reduced efficacy. There are also opportunities for synergy between systemic therapy and radiotherapy to improve patient outcomes. Breast Cancer Trials, as Australia and New Zealand’s multidisciplinary breast cancer clinical trials organisation, is well positioned alongside TROG to conduct trials of high scientific merit with an ‘optimisation’ focus. This involves giving an individual patient as much treatment as they need, but no more, to facilitate best outcomes with minimal toxicity. This presentation will focus on the current intersection between radiotherapy and systemic therapy, along with future directions.