Multiple randomized trials and their meta-analysis have demonstrated an overall survival benefit from postmastectomy radiotherapy (PMRT) in women with node-positive breast cancer. However, none of the patients treated in these trials received neoadjuvant chemotherapy, which is now an increasingly common approach. It is unclear how best to apply data from trials conducted in patients treated with adjuvant chemotherapy to this population. To illuminate these issues, this article first reviews the history of PMRT and the current indications for its use based on contemporary data. It focuses on the ways in which staging and outcomes differ for patients who undergo neoadjuvant chemotherapy before mastectomy (as compared with those who receive postoperative adjuvant therapy) and how pathologic features such as response to therapy are correlated with recurrence and survival outcomes. It highlights key information obtained from analysis of the pooled data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) prospective neoadjuvant chemotherapy trials B-18 and B-27 and separate retrospective single-institution studies; this includes the low risk of locoregional recurrence in early-stage patients in whom a pathologic complete response (pCR) was achieved after neoadjuvant chemotherapy without PMRT and the high risk of recurrence in patients with stage III disease, even in the setting of a pCR. It also discusses the ongoing NSABP B-51/Radiation Therapy Oncology Group 1304 and Alliance A011202 trials, which will provide information on whether PMRT can be omitted in patients who have a pathologic complete response (pCR) in the lymph nodes, and whether axillary lymph node dissection will improve recurrence rates compared with sentinel lymph node biopsy and radiotherapy in patients who do not achieve a pCR in the lymph nodes. Finally, it identifies directions for future research.