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mRNA cap methylation is a conserved epitranscriptomic modification that shapes transcript fate and enables host RNA to be distinguished from foreign RNA during viral infections. mRNA capping occurs co-transcriptionally to generate the 7-methylguanosine (m⁷G) cap0 structure, which is essential for RNA stability, splicing, nuclear export, and translation. Subsequent 2′-O-methylation of the first and second transcribed nucleotides by cap methyltransferases CMTR1 and CMTR2 produces cap1 and cap2 structures, respectively, in all eukaryotes except yeast. While cap1 modification is present on more than 90% of mRNAs, cap2 methylation occurs in ~10–60% of transcripts, depending on cell type and organism. How these 2′-O-methylation modifications at the 5′-end of mRNA selectively regulate specific gene expression programs remains an unresolved question. In this talk, I will present our findings on mRNA cap methylation in the developing cerebellum based on studies of CMTR1 and CMTR2 conditional knockout mice.