Mastectomy has long been regarded as the standard of care for local relapse after breast-conserving surgery and radiation therapy. Due to the perceived heightened risk of toxicity, a similar rationale and approach is often employed for patients that develop a new breast cancer after being treated with mantle field irradiation for Hodgkin’s disease or lymphoma. Patients are increasingly requesting additional breast conserving treatment following an initial excellent cosmetic outcome before recurrence. After receiving whole breast external beam radiation therapy, most recurrences occur within or close to the quadrant of the index lesion. Partial breast irradiation (PBI) can target the areas at greatest risk for residual microscopic disease while minimizing the volume of healthy breast tissue re-irradiated. Studies with short follow up suggest that catheter-based interstitial brachytherapy or limited-field external beam radiotherapy can be safely delivered to the breast following an initial course of external bream radiotherapy with acceptable outcomes. A prospective, randomized Phase II multicenter trial to evaluate repeat lumpectomy followed by PBI for in-breast tumor recurrence is warranted to explore the role of repeat breast-conservation.