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Purpose: To provide an overview of the major randomized trials that support the use of hypofractionated post-mastectomy radiation therapy for locally advanced breast cancer patients. Methods and Materials: PubMed was systematically reviewed for publications reporting use of of hypofractionated radiation therapy in patients requiring post-mastectomy radiation. Results: Standard fractionation, which is typically delivered over 5 to 7 weeks, is considered the standard of care in setting of post-mastectomy radiation therapy (PMRT). Modern data has helped to establish hypofractionated whole breast irradiation, which consists of a 3- to 4-week regimen, as a new standard of care for early-stage breast cancer. Hypofractionated whole breast irradiation has also laid the groundwork for the exploration of a hypofractionated approach in the setting of hypofractionated post-mastectomy radiation therapy. Conclusions: While standard fractionation remains the most commonly utilized regimen for PMRT, recently published trials support the safety and efficacy of a hypofractionated approach. Ongoing trials are further investigating the use of hypofractionated PMRT.