The 5' cap of mRNA contains a reversible modification, m6Am, which influences mRNA stability. This study shows that m6Am, a modified nucleotide adjacent to the 7-methylguanosine cap, is reversibly methylated and affects the stability of mRNA. Using a transcriptome-wide map of m6Am, the researchers found that m6Am-initiated transcripts are more stable than those starting with other nucleotides. This stability is due to resistance to the mRNA-decapping enzyme DCP2. Additionally, the fat mass and obesity-associated protein (FTO) selectively demethylates m6Am, reducing the stability of m6Am-containing mRNAs. These findings demonstrate that the methylation status of m6Am in the 5' cap is a dynamic and reversible epitranscriptomic modification that determines mRNA stability. The study also shows that FTO targets m6Am in a 7-methylguanosine cap-dependent manner and that m6Am mRNAs exhibit increased half-life in cells. Furthermore, m6Am mRNAs are less susceptible to decapping and microRNA-mediated mRNA degradation. The results suggest that m6Am contributes to the variability in mRNA responses to microRNAs and that the presence of m6Am in the 5' cap is a key determinant of mRNA stability and abundance. The study highlights the importance of epitranscriptomic modifications in gene expression regulation and their potential impact on cellular processes such as mRNA stability and degradation.The 5' cap of mRNA contains a reversible modification, m6Am, which influences mRNA stability. This study shows that m6Am, a modified nucleotide adjacent to the 7-methylguanosine cap, is reversibly methylated and affects the stability of mRNA. Using a transcriptome-wide map of m6Am, the researchers found that m6Am-initiated transcripts are more stable than those starting with other nucleotides. This stability is due to resistance to the mRNA-decapping enzyme DCP2. Additionally, the fat mass and obesity-associated protein (FTO) selectively demethylates m6Am, reducing the stability of m6Am-containing mRNAs. These findings demonstrate that the methylation status of m6Am in the 5' cap is a dynamic and reversible epitranscriptomic modification that determines mRNA stability. The study also shows that FTO targets m6Am in a 7-methylguanosine cap-dependent manner and that m6Am mRNAs exhibit increased half-life in cells. Furthermore, m6Am mRNAs are less susceptible to decapping and microRNA-mediated mRNA degradation. The results suggest that m6Am contributes to the variability in mRNA responses to microRNAs and that the presence of m6Am in the 5' cap is a key determinant of mRNA stability and abundance. The study highlights the importance of epitranscriptomic modifications in gene expression regulation and their potential impact on cellular processes such as mRNA stability and degradation.