Functional heterogeneity within tumors presents a significant therapeutic challenge. Here we show that quiescent, therapy-resistant Sox2+ cells propagate sonic hedgehog subgroup medulloblastoma by a mechanism that mirrors a neurogenic program. Rare Sox2+ cells produce rapidly cycling doublecortin+ progenitors that, together with their postmitotic progeny expressing NeuN, comprise tumor bulk. Sox2+ cells are enriched following anti-mitotic chemotherapy and Smoothened inhibition, creating a reservoir for tumor regrowth. Lineage traces from Sox2+ cells increase following treatment, suggesting that this population is responsible for relapse. Targeting Sox2+ cells with the antineoplastic mithramycin abrogated tumor growth. Addressing functional heterogeneity and eliminating Sox2+ cells presents a promising therapeutic paradigm for treatment of sonic hedgehog subgroup medulloblastoma. Display omitted •Sonic hedgehog medulloblastoma growth is driven by rare quiescent Sox2+ cells•Fate mapping and transplantation show that Sox2+ cells are tumor-propagating cells•Sox2+ medulloblastoma cells are resistant to Smoothened inhibition•Targeting Sox2+ medulloblastoma cells with mithramycin blocks tumor growth Vanner et al. show that quiescent SOX2+ cells are SHH subtype medulloblastoma (MB)-propagating cells (MPCs) in mice and that patients having SHH MB with a high MPC signature have a poor outcome. Sox2+ cells are enriched following antimitotic or SHH pathway-targeted therapy but can be inhibited using mithramycin.