Sonic Hedgehog medulloblastoma (SHH-MB) is the most prevalent molecular subtype of medulloblastoma, a common and deadly pediatric brain malignancy. Significant effort has been invested into preclinical development of inhibitors directed at downstream targets of the SHH pathway, such as the stem cell factor and proto-oncogene SOX9. The cover depicts immunofluorescence imaging of SHH-MB mouse tumor models, in which SOX9 expression is labeled in red and the glial marker GFAP is labeled in green. The authors demonstrate that, even though SOX9 expression is an intrinsic feature of SHH-MB that is not shared by other medulloblastoma subtypes, interference with SOX9 expression did not significantly alter SHH-MB development or disease course. They therefore argue that efforts to develop SOX9 inhibitors for clinical use will likely not provide significant benefit for SHH-MB patients if advanced to the clinic, and suggest that alternative targets must be identified. For more information, see the Highlight on page 1793 and the article on page 1831.