YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. YTHDF3 is a cytoplasmic protein that binds N6-methyladenosine (m6A)-modified RNA. This study shows that YTHDF3 promotes protein synthesis in synergy with YTHDF1 and affects methylated mRNA decay through YTHDF2. Cells deficient in all three YTHDF proteins experience the most dramatic accumulation of m6A-modified transcripts. These results indicate that YTHDF3, along with YTHDF1 and YTHDF2, plays critical roles in accelerating the metabolism of m6A-modified mRNAs in the cytoplasm. All three YTHDF proteins may act in an integrated and cooperative manner to impact fundamental biological processes related to m6A RNA methylation. The study reveals that YTHDF3 binds m6A in cells and shares mRNA targets with YTHDF1 and YTHDF2. YTHDF3 facilitates translation of its RNA targets and interacts with YTHDF1 to cooperatively promote translation. YTHDF3 also functions in the cytosol to regulate the decay of m6A-modified transcripts. The three YTHDF proteins form an interconnected network in the cytosol, with YTHDF1 involved in translation regulation, YTHDF2 in accelerating mRNA decay, and YTHDF3 acting as a hub for fine-tuning the RNA accessibility of YTHDF1 and YTHDF2. These three mRNA pools controlled by YTHDF1-3 could be interchangeable and highly dynamic, resulting in an interconnected and dynamic mRNA modulation through m6A. The study also shows that YTHDF3 may interact with other protein partners to negatively impact translation. The results suggest a coordinated functional interaction of the three YTHDF proteins inside cells. YTHDFs share hundreds of common targets and interact with the common targets with an apparent temporal order. YTHDF3 affects translation and decay of methylated mRNAs through cooperation with YTHDF1 and YTHDF2. YTHDF3 could noticeably affect functions performed by the other two YTHDFs. Therefore, besides the reversible, dynamic, and non-stoichiometric nature of the m6A modification itself, a divergent expression pattern of YTHDF proteins in different cell types or developmental stages could provide temporal-spatial control of protein production from m6A-modified transcripts. The integrated function of YTHDFs is further exemplified by recent studies on how the m6A modification on HIV RNA affects viral gene expression. Overexpression of any of the YTHDFs resulted in a similar effect of promotion of protein synthesis from HIV RNAs, and inhibition of HIV-1 virus infection by decreasing HIV-1 reverse transcription.YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. YTHDF3 is a cytoplasmic protein that binds N6-methyladenosine (m6A)-modified RNA. This study shows that YTHDF3 promotes protein synthesis in synergy with YTHDF1 and affects methylated mRNA decay through YTHDF2. Cells deficient in all three YTHDF proteins experience the most dramatic accumulation of m6A-modified transcripts. These results indicate that YTHDF3, along with YTHDF1 and YTHDF2, plays critical roles in accelerating the metabolism of m6A-modified mRNAs in the cytoplasm. All three YTHDF proteins may act in an integrated and cooperative manner to impact fundamental biological processes related to m6A RNA methylation. The study reveals that YTHDF3 binds m6A in cells and shares mRNA targets with YTHDF1 and YTHDF2. YTHDF3 facilitates translation of its RNA targets and interacts with YTHDF1 to cooperatively promote translation. YTHDF3 also functions in the cytosol to regulate the decay of m6A-modified transcripts. The three YTHDF proteins form an interconnected network in the cytosol, with YTHDF1 involved in translation regulation, YTHDF2 in accelerating mRNA decay, and YTHDF3 acting as a hub for fine-tuning the RNA accessibility of YTHDF1 and YTHDF2. These three mRNA pools controlled by YTHDF1-3 could be interchangeable and highly dynamic, resulting in an interconnected and dynamic mRNA modulation through m6A. The study also shows that YTHDF3 may interact with other protein partners to negatively impact translation. The results suggest a coordinated functional interaction of the three YTHDF proteins inside cells. YTHDFs share hundreds of common targets and interact with the common targets with an apparent temporal order. YTHDF3 affects translation and decay of methylated mRNAs through cooperation with YTHDF1 and YTHDF2. YTHDF3 could noticeably affect functions performed by the other two YTHDFs. Therefore, besides the reversible, dynamic, and non-stoichiometric nature of the m6A modification itself, a divergent expression pattern of YTHDF proteins in different cell types or developmental stages could provide temporal-spatial control of protein production from m6A-modified transcripts. The integrated function of YTHDFs is further exemplified by recent studies on how the m6A modification on HIV RNA affects viral gene expression. Overexpression of any of the YTHDFs resulted in a similar effect of promotion of protein synthesis from HIV RNAs, and inhibition of HIV-1 virus infection by decreasing HIV-1 reverse transcription.