Radiotherapy is an important component in the treatment of breast cancer. However, the individual tumor response to radiation is variable, reflecting both the intrinsic properties of the tumor and its microenvironment as well as the different, inherited sensitivity of the patient's normal tissue when exposed to the effect of ionizing radiation. These differences have inspired research to discover the underlying signal transduction pathways and to understand when they pertain to the tumor, the host or both. In fact, understanding the mechanisms underlying radiosensitivity of breast cancer not only does it permit to design more effective radiation treatments, but it sheds light on the complexities of tumor-host interactions in this disease.