Daily conventionally fractionated breast irradiation over 5–7 weeks is costly and inconvenient. Its use is associated with disparities in both the delivery of quality care and outcomes for vulnerable populations. Alternatively, daily hypofractionated breast irradiation delivered over 3 weeks exhibits equal efficacy and toxicity profiles. Today, a new generation of accelerated radiotherapy for breast cancer has emerged. Once-weekly hypofractionated breast irradiation has been tested in pilot and large randomized studies and the initial data appear promising. As the data mature, this new approach has implications for cost-efficacy and provision of radiotherapy services. The purpose of this review is to explore the evolution of once-weekly hypofractionated breast irradiation including our ongoing institutional clinical trial at the University of Louisville.