Meta-analyses of tens of thousands of women treated with radiation as a component of their breast cancer treatment have shown that radiation improves overall survival from breast cancer in women with early stage and advanced disease. However, data suggest that breast cancer stem/progenitor cells can be enriched after radiation and that breast cancer stem/progenitor clonogens are particularly resistant to radiation. Potentially resistant breast cancer stem/progenitor populations appear to be over-represented in estrogen receptor negative breast cancer and indeed, clinically these cancers are more resistant to radiation than estrogen receptor positive breast cancers. Emerging pre-clinical data suggest that targeting cancer stem/progenitor survival pathways may lead to effective radiosensitization in subgroups of patients with resistant disease. Herein, preclinical studies are reviewed in the context of the clinical framework.