Primary systemic therapy is not only used in patients with locally advanced inoperable non-metastatic breast cancer but also for operable stage II and III cancer aimed at breast conservation. The indications for local-regional radiotherapy for patients who receive primary systemic therapy are still evolving. The purpose of this article is to provide a comprehensive discussion of how primary systemic therapy in operable breast cancer patients could affect the indications of radiotherapy to optimize local-regional treatment. An overview of available literature data regarding neoadjuvant treatment and radiotherapy is analyzed and discussed. Considering the variability of data on this issue, an appropriate approach could still be to tailor treatment decision to the individual clinical case.