There is compelling evidence that many solid cancers are organized hierarchically and contain a small population of cancer stem cells (CSCs). It seems reasonable to suggest that a cancer cure can be achieved only if this population is eliminated. Unfortunately, there is growing evidence that CSCs are inherently resistant to radiation, and perhaps other cancer therapies. In general, success or failure of standard clinical radiation treatment is determined by the 4 R's of radiobiology: repair of DNA damage, redistribution of cells in the cell cycle, repopulation, and reoxygenation of hypoxic tumor areas. We relate recent findings on CSCs to these four phenomena and discuss possible consequences.