N6-methyladenosine (m6A) is a prevalent internal modification in messenger RNA (mRNA) across all higher eukaryotes. Despite its essential role in cell viability and development, the exact function of m6A remains unclear. Recent discoveries of m6A demethylases have highlighted the importance of m6A in biological functions and disease. This study demonstrates that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) protein to regulate mRNA stability. Over 3,000 cellular RNA targets of YTHDF2 were identified, most of which are mRNAs but also include non-coding RNAs. The C-terminal domain of YTHDF2 selectively binds to m6A-containing mRNA, while the N-terminal domain localizes the YTHDF2-mRNA complex to mRNA decay sites. YTHDF2 knockdown leads to reduced translation efficiency and prolonged mRNA lifetimes, indicating its role in mRNA degradation. The study provides a transcriptome-wide identification of YTHDF2-RNA interaction and a mechanistic model for m6A function mediated by this m6A-binding protein, highlighting the dynamic regulation of mRNA stability and localization through m6A "readers".N6-methyladenosine (m6A) is a prevalent internal modification in messenger RNA (mRNA) across all higher eukaryotes. Despite its essential role in cell viability and development, the exact function of m6A remains unclear. Recent discoveries of m6A demethylases have highlighted the importance of m6A in biological functions and disease. This study demonstrates that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) protein to regulate mRNA stability. Over 3,000 cellular RNA targets of YTHDF2 were identified, most of which are mRNAs but also include non-coding RNAs. The C-terminal domain of YTHDF2 selectively binds to m6A-containing mRNA, while the N-terminal domain localizes the YTHDF2-mRNA complex to mRNA decay sites. YTHDF2 knockdown leads to reduced translation efficiency and prolonged mRNA lifetimes, indicating its role in mRNA degradation. The study provides a transcriptome-wide identification of YTHDF2-RNA interaction and a mechanistic model for m6A function mediated by this m6A-binding protein, highlighting the dynamic regulation of mRNA stability and localization through m6A "readers".