This study reveals that m6A RNA methylation is critical for the self-renewal and tumorigenesis of glioblastoma stem cells (GSCs). The m6A modification is catalyzed by the methyltransferase complex containing METTL3 and METTL14. Knockdown of METTL3 or METTL14 significantly promotes GSC growth, self-renewal, and tumorigenesis, while overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses these processes. Inhibition of FTO also suppresses tumor progression and prolongs the lifespan of GSC-grafted mice. m6A sequencing shows that METTL3 or METTL14 knockdown alters mRNA m6A enrichment and expression of genes with critical functions in GSCs. These findings suggest that the m6A mRNA methylation machinery is a promising therapeutic target for glioblastoma. The study also identifies that m6A modification regulates gene expression in GSCs, with specific genes like ADAM19 playing a key role in GSC self-renewal and tumorigenesis. The results indicate that targeting m6A methylation could be a promising strategy for glioblastoma therapy.This study reveals that m6A RNA methylation is critical for the self-renewal and tumorigenesis of glioblastoma stem cells (GSCs). The m6A modification is catalyzed by the methyltransferase complex containing METTL3 and METTL14. Knockdown of METTL3 or METTL14 significantly promotes GSC growth, self-renewal, and tumorigenesis, while overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses these processes. Inhibition of FTO also suppresses tumor progression and prolongs the lifespan of GSC-grafted mice. m6A sequencing shows that METTL3 or METTL14 knockdown alters mRNA m6A enrichment and expression of genes with critical functions in GSCs. These findings suggest that the m6A mRNA methylation machinery is a promising therapeutic target for glioblastoma. The study also identifies that m6A modification regulates gene expression in GSCs, with specific genes like ADAM19 playing a key role in GSC self-renewal and tumorigenesis. The results indicate that targeting m6A methylation could be a promising strategy for glioblastoma therapy.