Accumulating experimental evidence supports the existence of a subpopulation of cancer cells known as cancer stem cells (CSCs). These cells comprise a small portion of most tumors and are uniquely able to regenerate an entire tumor. This population of cells may express different cell surface markers than most other tumor cells; in breast cancer, some evidence suggests that CSCs exhibit a CD44⁺/CD24^−/phenotype. In addition to their role as a progenitor population, CSCs appear to be especially resistant to anticancer therapies, including radiotherapy. The radio-resistance of CSCs appears to be mediated by both the activation of pro-survival pathways and the inhibition of pro-apoptotic pathways. Early data suggest that activation of the NFκB pathway is integral to radio-resistance: NFκB initiates a pro-survival pathway by enhancing DNA repair through the control of cell cycle checkpoints, and NFκB also contributes to radio-resistance through the inhibition of apoptosis. Importantly, the NFκB pathway is initiated by the HER2 signaling pathway, itself an important therapeutic target in breast cancer. There is emerging evidence that NFκB may feedback to enhance HER2 signaling, a positive feedback mechanism dubbed the HER2-NFκB-HER2 loop. The molecular mechanisms underlying CSC-related radio-resistance are not yet fully elucidated. It is hoped that clarification of these pathways will yield insights into the design of pharmaceuticals to overcome radio-resistance (and chemo-resistance) and render the all-important CSCs vulnerable to cytotoxic therapies.