This study investigates the role of N6-methyladenosine (m6A) mRNA modification in glioblastoma stem cell (GSC) self-renewal and tumorigenesis. The authors found that knocking down key components of the m6A methyltransferase complex, METTL3 or METTL14, significantly promotes GSC growth, self-renewal, and tumorigenesis. Conversely, overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses GSC growth and self-renewal. Inhibition of FTO also suppresses tumor progression and prolongs the lifespan of GSC-grafted mice. Transcriptome-wide m6A sequencing revealed that METTL3 or METTL14 knockdown alters mRNA m6A enrichment and expression of genes critical for GSC function, such as ADAM19. These findings identify m6A mRNA methylation as a promising therapeutic target for glioblastoma.This study investigates the role of N6-methyladenosine (m6A) mRNA modification in glioblastoma stem cell (GSC) self-renewal and tumorigenesis. The authors found that knocking down key components of the m6A methyltransferase complex, METTL3 or METTL14, significantly promotes GSC growth, self-renewal, and tumorigenesis. Conversely, overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses GSC growth and self-renewal. Inhibition of FTO also suppresses tumor progression and prolongs the lifespan of GSC-grafted mice. Transcriptome-wide m6A sequencing revealed that METTL3 or METTL14 knockdown alters mRNA m6A enrichment and expression of genes critical for GSC function, such as ADAM19. These findings identify m6A mRNA methylation as a promising therapeutic target for glioblastoma.