Purpose of Review <p>This review summarizes the clinical and radiobiologic data regarding hypofractionation in breast cancer, applying it to the postmastectomy setting in a comprehensive review of recent and ongoing trial data.</p> Recent Findings <p>Experience with hypofractionated postmastectomy radiation in the 1960s demonstrated high rates of brachial plexopathy, prompting a trend towards conventionally fractionated schemas. Subsequent radiobiologic data identified that breast cancer has a relatively low α/β ratio (approximately 4&#xa0;Gy). Following breast conservation, hypofractionation has maximized the therapeutic window by eradicating tumor while minimizing normal tissue effects. Postmastectomy patients, however, usually require comprehensive regional nodal irradiation and often opt for reconstruction. Five trials have shown excellent disease control and toxicity profiles with hypofractionation, with those in the modern era also supporting hypofractionation after reconstruction.</p> Summary <p>Hypofractionated postmastectomy radiation is at minimum noninferior in complication rates and quality of life metrics and should be widely accepted as a standard option for appropriate patients in the post-mastectomy setting.</p>