Radiation therapy plays an integral role in the multidisciplinary management of breast cancer. In appropriately selected patients, radiotherapy not only prevents local recurrences by eliminating residual disease but also results in improved survival. However, not all patients have the same risk of harboring residual locoregional disease, resulting in considerable controversy regarding the role of radiotherapy in individual scenarios. Evidence from clinical trials and observational data analyses can help identify which patients with breast cancer are most likely to achieve a net benefit from adjuvant radiation therapy, both after lumpectomy and mastectomy. Additionally, evidence is emerging now about novel approaches in breast radiotherapy that may reduce burden or toxicity in ways that can optimize the therapeutic ratio, including hypofractionated whole breast radiation, accelerated partial breast irradiation (APBI), intensity-modulated radiation (IMRT), and cardiac avoidance techniques. The objective of this chapter is to review both established and emerging evidence regarding these important issues in an effort to clarify the rationale for increasingly complex and individualized decisions regarding breast radiotherapy.