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Epigenetic alterations, such as alterations of histone modification and DNA methylation, occur in a genome-wide manner under precancerous conditions resulting from hepatitis B virus (HBV) or hepatitis C virus (HCV) infection followed by chronic hepatitis and cirrhosis, or aberrant lipogenesis and abnormal metabolism of reactive oxygen species that characterize the pathophysiology of non-alcoholic steatohepatitis (NASH). Once DNA methylation alterations occur at the precancerous stage, they are stably preserved on DNA double strands through methylation maintenance by DNA methyltransferase 1 (DNMT1). DNA methylation alterations associated with abnormalities of DNA methyltransferase, such as overexpression of DNMT1 and splicing alterations of DNMT3B, participate in multistage hepatocarcinogenesis from the precancerous stage to the malignant progression stage and are correlated with aggressiveness of hepatocellular carcinomas (HCCs) and poorer outcome of affected patients. A number of tumor-related genes, such as ATK3, APC, BMP4, CCL20, CDH1, CDKN2A, CDKN2B, CSPG2, DAB2IP, DCC, DLC1, DPT, DPYSL3, EMILIN2, FZD7, GRASP, GSTP1, HIST1H4F, IGFALS, MGMT, MZB1, NAT2, NEFH, NFATC1, PAX4, PDSS2, PER3, PROZ, PYCARD, RASSF1A, SPDY1, RUNX3, SCGB1D1, SFN, SMPD3, SOCS1, TIMP3, TLX3, TM6SF1, TRIM33, TRIM58, WFDC6, WNK2 and ZFP41, are known to be silenced by DNA hypermethylation in human HCCs. It is believed that DNA methylation alterations could be excellent biomarkers for carcinogenetic risk estimation and prognostication. To facilitate clinical application of DNA methylation diagnosis, a scaled-down device that allows quick and accurate analysis, even in small hospitals and clinics, is now being developed. One therapeutic strategy against HCC proliferation could involve a combination of epigenetic modifiers, such as a DNA methylation inhibitor, a histone deacetylase inhibitor and an S-adenosylhomocysteine hydrolase inhibitor, to sensitize cancer cells to conventional chemotherapies, in addition to eradication of hepatitis viruses for personalized and/or pre-emptive medical care.