To accommodate the variable environments, bacterial cells often need to take swift changes on metabolism while keep their genomic sequence unchanged. Thus, epigenetic regulation becomes an important way for bacteria because no genomic alteration is required. As one of the DNA modifications, DNA methylation is the most well-known epigenetic tools among all the organisms. Here in this review, we gave a comprehensive introduction of two orphan methyltransferases Dam (DNA adenine methyltransferase) and CcrM (Cell cycle-regulated methyltransferase), as examples of epigenetic regulation in prokaryotes. We majorly talked about their role in bacterial DNA replication initiation, DNA mismatch repair, regulation of gene expression, virulence and phase variation. Moreover, we also discussed the trends in this field based on a newly-generated technology Chromosome Conformation Capture (3C) and a novel DNA phosphorothioate modification.