The last decade has seen major changes in the management of breast cancer. Heterogeneity regarding histology, therapeutic response, dissemination patterns, and patient outcome is evident. Molecular profiling provides an accurate tool to predict treatment outcome compared with classical clinicopathologic features. The genomic profiling unveiled the heterogeneity of breast cancer and identified distinct biologic subtypes. These advanced techniques were integrated into the clinical management; predicting systemic therapy benefit and overall survival. Utilizing genotyping to guide locoregional management decisions needs further characterization. In this chapter we will review available data on molecular classification of breast cancer, their association with locoregional outcome, their radiobiological properties and radiotherapy considerations.