Radiotherapy (RT) plays an important role in the management of locally advanced breast cancer (BC). Postmastectomy RT has been shown to significantly reduce the risk of loco-regional failure and to improve disease free survival in high-risk women with BC. Many trials have shown a significant benefit in local control, disease-free and overall survival with the addition of RT for patients with stage II and III breast cancer. New perspectives are evaluating multiple biological variables that nowadays should be considered in clinical oncology for the prescription of postmastectomy radiation therapy. Tailored randomized trials are now ongoing to clarify the "grey zone" represented by the intermediate-risk group of patients (1-3 lymph nodes involved). We reviewed the major studies offered by literature with emphasis on the principal debated issues.