Intraoperative radiotherapy (IORT) is a promising approach for delivering accelerated, partial breast irradiation (APBI). Condensing the entire therapeutic dose into a single fraction, delivering the treatment at the time of lumpectomy in the operating room, and with the ability to spare normal surrounding tissue to a greater extent than perhaps any other form of APBI, IORT offers many potential benefits. Whether a single fraction is able to provide effective local control, and whether long term tissue tolerance to a large single dose is acceptable, are the greatest concerns for this approach. Breast IORT trials conducted thus far are encouraging. This review will first describe the clinical trials that provided the groundwork for single-fraction breast IORT, and will then summarize ongoing phase I/II and phase III clinical trials evaluating this potentially safe and effective form of APBI.