Historically, prognosis and treatment decision making for breast cancer patients have been dictated by the anatomic extent of tumor spread. However, in recent years, "breast cancer" has proven to be a collection of unique phenotypes with distinct prognoses, patterns of failure, and treatment responses. Recent advances in biologically based assays and targeted therapies designed to exploit these unique phenotypes have profoundly altered systemic therapy practice patterns and treatment outcomes. Data associating locoregional outcomes with tumor biology are emerging. However, the likelihood of obtaining level I evidence for fundamental radiation therapy questions within each of the specific subtypes in the immediate future is low. As such, this review aims to summarize the existing data and provide practical context for the incorporation of breast tumor biology into clinical practice.