The presence of a subpopulation of cells within tumors, so-called cancer stemlike cells, that is uniquely capable of reestablishing the tumor during and after definitive radio(chemo)therapy and must be effectively controlled for a long-term cure is being increasingly appreciated. The existence and physiology of a rare cancer cell population, termed cancer cell clonogens, with similar properties has been extensively described in the radiobiology literature for several decades based on studies using tumor cells transplanted into syngeneic or immunodeficient animals. The earlier studies have identified important features that govern tumor establishment; tumor growth and homeostasis; and therapeutic resistance, including clonogen number, tumor type, vascular status, hypoxia, repopulation dynamics during treatment, and immunologic and microenvironmental status. These discoveries led to therapeutic strategies, some of which have shown efficacy and have become current standard clinical practice (eg, concomitant boost and concurrent radio chemotherapy). Although the identity of cancer stemlike cells and cancer cell clonogens has not been definitively shown, recent characterization of molecular signaling pathways controlling stem cells and their microenvironmental niche combined with the earlier findings on clonogen physiology may now lead to the development of molecularly targeted strategies to overcome therapeutic resistance of this rare subpopulation of tumor cells. Along these lines, we describe 3 unique treatment settings (ie, before, during, and after definitive radio[chemo]therapy) in which molecularly targeted approaches might specifically counteract cancer stemlike cell resistance mechanisms and enhance the curative efficiency of radio(chemo)therapy.