This study investigates the role of a specific subset of quiescent endogenous tumor cells in the recurrence of glioblastoma multiforme (GBM) following chemotherapy. Using a genetically engineered mouse model, researchers identified a subset of tumor cells labeled by the *Nestin-ΔTK-IRES-GFP* (*Nes-ΔTK-GFP*) transgene, which also labels quiescent adult neural stem cells in the subventricular zone (SVZ). After administration of temozolomide (TMZ), a drug that transiently arrests tumor growth, pulse-chase experiments revealed that tumor recurrence is driven by this *Nes-ΔTK-GFP* positive cell population. Chronic administration of ganciclovir (GCV), which specifically targets dividing cells, effectively eliminated these quiescent cells, significantly reducing tumor growth and improving survival. Combined treatment with TMZ and GCV further impeded tumor development, suggesting that targeting both rapidly proliferating and quiescent tumor cells is crucial for effective therapy. These findings highlight the existence of a quiescent subset of endogenous glioma cells that sustain long-term tumor growth and provide insights into potential therapeutic strategies for GBM.This study investigates the role of a specific subset of quiescent endogenous tumor cells in the recurrence of glioblastoma multiforme (GBM) following chemotherapy. Using a genetically engineered mouse model, researchers identified a subset of tumor cells labeled by the *Nestin-ΔTK-IRES-GFP* (*Nes-ΔTK-GFP*) transgene, which also labels quiescent adult neural stem cells in the subventricular zone (SVZ). After administration of temozolomide (TMZ), a drug that transiently arrests tumor growth, pulse-chase experiments revealed that tumor recurrence is driven by this *Nes-ΔTK-GFP* positive cell population. Chronic administration of ganciclovir (GCV), which specifically targets dividing cells, effectively eliminated these quiescent cells, significantly reducing tumor growth and improving survival. Combined treatment with TMZ and GCV further impeded tumor development, suggesting that targeting both rapidly proliferating and quiescent tumor cells is crucial for effective therapy. These findings highlight the existence of a quiescent subset of endogenous glioma cells that sustain long-term tumor growth and provide insights into potential therapeutic strategies for GBM.