N⁶-methyladenosine (m⁶A) has been identified as the most abundant internal modification of messenger RNA in eukaryotes. m⁶A modification is involved in cell fate determination in yeast^, and embryo development in plants^,. Its mammalian function remains unknown but thousands of mammalian mRNAs and long non-coding RNAs (lncRNAs) show m⁶A modification^, and m⁶A demethylases are required for mammalian energy homeostasis and fertility^,. We identify two proteins, the putative m⁶A MTase, methyltransferase-like 3 (Mettl3; ref. ), and a related but uncharacterized protein Mettl14, that function synergistically to control m⁶A formation in mammalian cells. Knockdown of Mettl3 and Mettl14 in mouse embryonic stem cells (mESCs) led to similar phenotypes, characterized by lack of m⁶A RNA methylation and lost self-renewal capability. A large number of transcripts, including many encoding developmental regulators, exhibit m⁶A methylation inversely correlated with mRNA stability and gene expression. The human antigen R (HuR) and microRNA pathways were linked to these effects. This gene regulatory mechanism operating in mESCs through m⁶A methylation is required to keep mESCs at their ground state and may be relevant to thousands of mRNAs and lncRNAs in various cell types.