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In the last decade, the breast cancer therapeutic landscape has significantly evolved with an array of targeted therapies (i.e., antibody-drug conjugates and immunotherapy agents) now in clinical use or in late clinical development. These biological agents can impair cancer cell proliferation (e.g., cyclin-dependent kinase 4 and 6 inhibitors -CDK4/6i- and anti-HER therapies), survival (e.g., PI3K and mTOR inhibitors and PARP inhibitors) and the ability to be recognized and destroyed by the immune system (e.g., immunotherapies). A boost to this evolving scenario is due to the advent of innovative preclinical models that reduce the lag-time between identification of tumor vulnerabilities, development of anti-cancer agents, and subsequent clinical applicability. These new therapeutic measures need to be integrated with local treatments, particularly with radiation therapy (RT) in both curative and advanced settings. Unfortunately, preclinical findings are frequently not confirmed in the clinic. These new targeted agents will undoubtedly affect tumor biology ultimately impacting on response to RT. Apart from an effect on tumor, we also need to study safety. For each drugs class, available literature across all phases of research, form preclinical to clinical setting will be overviewed. Prospective and retrospective trials, case series and case reports reporting safety data about RT and novel drug combination have been explored. The overall level-of-evidence is low and the recommendation on a safe integration is often uncertain. The setting of disease, intent of treatment, site, volume, dose, and fractionation of irradiation can significantly affect the safety of an integrated treatment. For the above-mentioned reasons, a case-by-case multidisciplinary approach should be strongly encouraged. An international consensus statement initiative, with the endorsement of the leading professionals’ community for breast cancer care and ESTRO is ongoing. This talk will overview preclinical and clinical evidence on how targeted agents and RT could be combined to help physicians in their daily clinical practice and to improve the clinical management of breast cancer patients.