Unstable cytokeratins are associated with tumor transformation in the development of human hepatocellular carcinoma. We previously demonstrated that the cytokeratin 18 was modulated and that a histone H3-specific modification occured, among members of the histone family, during the development of human hepatocellular carcinoma. Evidence suggested that the modification of histone H3 was highly correlated with the modulation of cytokeratin 18 and probably plays an important role in tumorigenesis of hepatocytes. Aberrant expression of histone deacetylase leading to imbalance between acetylation and deacetylation of histones may exhibit regulatory roles in tumor transformation. Recently we found that overexpression of histone deacetylase-1 and hypoacetylation of histone H3 were associated with hepatocellular carcinoma. The underlying roles of histone H3 modulation are discussed in this mini-review article.