The methylome is defined as a map of DNA methylation patterns at single-base resolution. DNA methylation in bacteria was first discovered as a function of restriction–modification (R-M) systems. R-M systems in Helicobacter pylori, like those in other bacteria, are important host-specificity determinants that provide protection against foreign DNA. Moreover, the gene regulatory role of the methyltransferase (Mtase) unit of various Helicobacter pylori R-M systems is being increasingly recognized. Recent advances in the application of single-molecule real-time (SMRT) DNA sequencing to analyse DNA methylation have revealed for the first time comprehensive pictures of the genome-wide distribution of methylation sites in various strains of H. pylori. The methylomic data published so far have not only confirmed the significant inter-strain diversity of H. pylori Mtases and their DNA methylation profiles, but also identified numerous novel Mtase target recognition sites. The precise knowledge of the nucleotide sequence of Mtase recognition sites and their distribution within the H. pylori genome will in turn enable researchers to more readily test hypotheses on how H. pylori Mtases function to orchestrate gene regulation and/or modulate virulence. Methylomic studies hold promise for providing a deeper understanding into the roles of H. pylori Mtase and R-M systems in the physiology, epigenetics and possibly also pathogenesis of this important human pathogen. Consequently, the knowledge gained will provide crucial insights into the potential application of H. pylori methylomes as novel biomarkers for the prediction of disease outcome and/or antibiotic susceptibility.