Radiation therapy is an integral component of the multimodal treatment of locally advanced breast cancer. Even after mastectomy and systemic therapy, occult residual disease in the chest wall and/or regional lymph nodes may serve as the source of morbid locoregional recurrence as well as the source of distant seeding or reseeding of metastases. Thus, postmastectomy radiation therapy offers substantial benefits in appropriately selected patients. This review article summarizes the data from randomized trials revealing a significant benefit from postmastectomy radiation therapy in patients with locally advanced disease as well as results from other relevant studies. It concludes with a summary of consensus guideline recommendations in this important area.