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.