Radiation after mastectomy is recommended for women with positive nodes, larger tumors, or positive margins. In addition to its role in reducing the risk for locoregional recurrence, it has an additive effect to the survival benefit seen with adjuvant systemic therapy. This article reviews the role of post-mastectomy radiation (PMRT) based on the recommendations in the 2007 NCCN Breast Cancer Clinical Practice Guidelines in Oncology and addresses the risk factors for recurrence after mastectomy. The data supporting both improvement in locoregional failure and survival are reviewed in detail. This article also discusses controversial areas in PMRT, including regional nodal radiation in women with 1 to 3 positive lymph nodes, PMRT in node-negative women with large tumors, and inclusion of internal mammary nodes. The final section discusses radiation field design and potential complications.