In CD133-positive tumor-propagating cells from glioblastoma, an intact actin cytoskeleton is required for elevated PLK1 activity, which in turn controls mitotic entry and cell polarity. Taken together, the data suggest a Plk1-driven polarity checkpoint, distinguishing CD133-positive tumor-propagating cells from autologous CD133-negative cells. Elevated PLK1 activity protects CD133-positive tumor-propagating cells from BRAF/MAPK inhibition and sensitizes them to Plk1 inhibition. Using immunocytochemistry, it was found that CD133 failed to localize to the membrane and in a polarized fashion in cells treated with actin polymerization inhibitor Latrunculin A. For details, see article by Lerner and colleagues on page 5355.