Recent studies have suggested that a specific small population of cells termed tumor-initiating cells (TICs) may be intrinsically resistant to therapy including radiation, and may therefore be the primary mediators of recurrence. Numerous targets are being explored using multiple approaches for their involvement in the self-renewal or survival as well as radioresistance of breast TICs. These studies will provide a broad range of compounds to be tested and to develop novel TIC radiosensitizers that will improve clinical outcome and decrease recurrence of cancer after radiation. In this review we will discuss recent efforts to identify and target these cells to selectively radiosensitize them with novel agents, as well as the TIC radiosensitizing potential of current therapies already in clinical use.