Medulloblastomas arising in Patched-1–deficient mice are an important model of the human disease, but it is unclear whether these genetically engineered tumors are organized as a hierarchy dependent on subpopulations of cells that have stem-cell properties. By applying stem-cell methodologies and functional assays in vitro and in vivo to the study of these Patched-1–deficient tumors, without or with p53-deficiency, the authors identified multipotent CD15+ medulloblastoma cells enriched for tumor-initiating ability in vitro and in vivo. Importantly, these cells show multiple lineage differentiation capacity after orthotopic injection in vivo and in vitro, based on serum-free adherent culture and clonal analysis. Although Patched-1–deficient medulloblastoma cells have been thought to only differentiate down neuronal lineages, in this image, the medulloblastoma cells demonstrate in vitro differentiation into cells that express markers of glial lineages, GFAP+ astrocytes (green) and CNPase+ oligodendrocytes (red). This study has implications for consideration of cell-of-origin of these tumors but, more importantly, offers new insights for understanding medulloblastoma growth in genetically engineered mice. For details, see the article by Ward and colleagues on page 4682 of this issue.