Adjuvant systemic therapy significantly reduces rates of distant recurrence and death. The effect of systemic therapy is not limited to reducing distant recurrences but also extends to reducing loco-regional recurrences, and rates of loco-regional recurrence have steadily declined over the past 25 years. This review focuses on the effect of adjuvant systemic therapy on rates of ipsilateral breast tumor recurrence following lumpectomy plus breast irradiation in several pivotal NSABP trials in early-stage breast cancer. J. Surg. Oncol. 2014 110:45–50. © 2014 Wiley Periodicals, Inc.