Postmastectomy radiotherapy (PMRT) reduces the risk of locoregional and distant recurrence and improves overall survival in women with lymph node-positive breast cancer. Because of stage migration and improvements in systemic therapy and other aspects of breast cancer care, the absolute benefit of PMRT and regional nodal irradiation may be small in some favorable subsets of patients with very low nodal burden, and newer consensus guidelines do not mandate PMRT in all node-positive cases. The use and need for PMRT may considerably complicate breast reconstruction after mastectomy and therefore mandates multidisciplinary input that takes into account patient choice given potential risk of acute and long-term toxicities, benefits, life expectancy, the biology of the tumor, plans for systemic therapy, and actual tumor burden. Management of axillary lymph node metastases is changing with selective use of axillary lymph node dissection for advanced disease, sentinel lymph node biopsy alone for clinically and pathologic node-negative cases receiving mastectomy, and targeted axillary dissection alone among patients with eradication of initial biopsy-proven nodal metastases with neoadjuvant systemic therapy use. In general, when the need for PMRT is anticipated, autologous reconstruction should be delayed. This comprehensive article reviews the current indications and implications regarding integration of breast cancer surgery and timing of reconstruction with optimum radiation delivery to achieve the best possible patient outcomes.