As key components of the ribosome and the most abundant RNA species, the rRNAs are modified during ribosome formation. N6-methyladenosine (m6A) is a conserved RNA modification occurring on different RNA species including rRNAs. Recently, it has been reported that ZCCHC4 and METTL5 are methyltransferases that mediate m6A modification of human 28S and 18S rRNA, respectively. The newly discovered biological functions of the two methyltransferases include regulation of mRNA translation, cell proliferation, cell differentiation, stress response, and other biological processes. Both of them, especially METTL5, have been proved to be associated with a variety of diseases such as intellectual disability, cancer, congenital dysplasia and have potential clinical application as biomarkers and therapeutic targets.© 2023 The Authors. Publishing services by Elsevier B.V.