Abstract Neoadjuvant therapy offers unique challenges and opportunities for the radiation oncologist. Classical indications for radiation have been rooted in the pathologic analysis of tissue resected prior to treating the patient with systemic therapy. However, in patients treated with neoadjuvant therapy, pathologic findings are frequently altered by the administration of systemic therapy, and thus classical indications for radiation may be clouded. Nevertheless, the degree of response to neoadjuvant therapy offers a novel prognostic factor which reflects intrinsic tumor biology and affords the opportunity for a new, precision approach to risk stratification and radiation therapy treatment decision making. To maximally capitalize on the information gained from treating a patient with neoadjuvant chemotherapy, patients must be meticulously staged, preferably by a multidisciplinary team, prior to initiation of systemic therapy. Ultrasound of the regional nodal basins including the low axillary, infraclavicular, supraclavicular, and internal mammary nodal chains with ultrasound-guided fine needle aspiration of radiographically abnormal nodes enables detailed mapping of the local-regional disease extent. Cross-sectional imaging with CT and/or PET/CT is also helpful to permit customized radiation field design after systemic therapy and surgery. These imaging studies are invaluable to the radiation oncologist and allow for optimal field design to facilitate cure. Additionally, nodal surgery prior to administration of systemic therapy, while helpful in documenting pre-treatment nodal status, results in loss of ability to accurately assess response to chemotherapy in the lymph nodes and is thus avoided in our practice. The available evidence indicates that patients experiencing a pathologic complete response have exceptional local-regional control. Accordingly, current randomized trials are exploring whether either radiation or surgery can be de-escalated within this context. In contrast, for patients with significant residual tumor burden following neoadjuvant chemotherapy, local-regional control outcomes are suboptimal for those with triple negative or HER2 positive disease. Novel strategies to escalate therapy with radiosensitizers or other biologic agents are needed for this population. Citation Format: Smith BD. ES6-3 Radiation implications post neoadjuvant therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES6-3.