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N 6-methyladenine (6mA) is the most prevalent DNA modification in prokaryotes. However, its presence and significance in eukaryotes remain elusive. Recently, with methodology advances in detection and sequencing of 6mA in eukaryotes, 6mA is back in the spotlight. Although multiple studies have reported that 6mA is an important epigenetic mark in eukaryotes and plays a regulatory role in DNA transcription, transposon activation, stress response, and other bioprocesses, there are some discrepancies in the current literature. We review the recent advances in 6mA research in eukaryotes, especially in mammals. In particular, we describe the abundance/distribution of 6mA, its potential role in regulating gene expression, identified regulators, and pathological roles in human diseases, especially in cancer. The limitations faced by the field and future perspectives in 6mA research are also discussed. 6mA is an abundant and functionally important modification in prokaryotes. Recently, emerging evidence supports its presence in eukaryotes, including mammals. In mammals, 6mA level is consistently low in normal mouse tissues, but varies in human cell lines or tissues. In addition, 6mA abundance is dynamic during normal development and disease progression. The genomic distribution of 6mA and its roles in gene regulation are tissue/biological process-dependent. Common features, distinct findings, and research limitations are discussed. Several proteins have been reported to function as 6mA writers or erasers in mammals, but some require further confirmation. Dysregulated 6mA levels and its regulators contribute to the development of human diseases including cancers. Targeting 6mA and its regulators holds potential in cancer treatment. [ABSTRACT FROM AUTHOR]