Postoperative treatment of early-stage breast cancer often includes radio- and chemo- therapy and, more recently, trastuzumab. Optimal timing, i.e. sequential or concomitant, of radiotherapy and systemic therapies to maximize efficacy and cosmetic outcome and minimize toxicity, is still controversial. This review analyzes the effects of different sequences after surgery as reported in phase III randomized studies and the most significant retrospective studies. Few randomized clinical trials investigated the optimal therapeutic sequence as most were designed to evaluate the efficacy of different chemotherapy schemes and schedules. Since end-points did not usually include the optimal timing of the two modalities, single participant centers were often free to decide whether radiotherapy should be administered or not, and what fields and schedules to use. Concomitant or sequential chemo- and radio-therapy were not associated with major differences in outcome. Concurrent administration is reserved for patients treated with CMF; it is not recommended when antracycline or taxanes are used, because of the increased risk of cutaneous, esophageal, cardiac and pulmonary toxicity. Although concurrent trastuzumab and radiotherapy seem feasible, trastuzumab induces cardiac damage. Even though it seems reversible, follow-ups in diverse studies were too short to assess the late side effects of concomitant trastuzumab and radiotherapy.