Significance: Recent research has shown that tumors contain a small subpopulation of stem-like cells that are more resistant to therapy and that are likely to produce second-line tumors. Recent Advances: Cancer stem-like cells (CSCs) have been characterized by a variety of markers, including, for a number of types of cancer, high expression of the plasma membrane protein CD133, which is also indicative of the increase of stemness of cultured cancer cells growing as spheres. Critical Issues: While the function of this protein has not yet been clearly defined, it may have a role in the stem-like phenotype of CSCs that cause (re-)initiation of tumors as well as their propagation. We hypothesize that CD133 selects for CSC survival against not only immunosurveillance mechanisms but also stress-induced apoptosis. Future Directions: High level of expression of CD133 may be a useful marker of more aggressive tumors that are recalcitrant toward established therapies. Compelling preliminary data indicate that drugs targeting mitochondria may be utilized as a novel, efficient cancer therapeutic modality.