N6-methyladenosine (mA) is the most abundant endogenous modification in eukaryotic RNAs. It plays important roles in various biological processes and diseases, including cancers. More and more studies have revealed that the deposition of mA is specifically regulated in a context-dependent manner. Here, we review the diverse mechanisms that determine the topology of mA along RNAs and the cell-type-specific mA methylomes. The exon junction complex (EJC) as well as histone modifications play important roles in determining the topological distribution of mA along nascent RNAs, while the transcription factors and RNA-binding proteins, which usually bind specific DNAs and RNAs in a cell-type-specific manner, largely account for the cell-type-specific mA methylomes. Due to the lack of specificity of mA writers and readers, there are still challenges to target the core mA machinery for cancer therapies. Therefore, understanding the mechanisms underlying the specificity of mA modifications in cancers would be important for future cancer therapies through mA intervention.