Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and thus constitutes a major health problem involving more than half a million new cases every year. During its promotion stage, HCC has been associated with defective apoptosis and increased cell proliferation. Only recently, gene expression has been shown to be regulated by epigenetics (reversible heritable changes in gene regulation that occur without a change in DNA sequence) involving changes in DNA methylation patterns as well as specific histone modifications. Throughout our proposal, we speculate that alterations in DNA methylation patterns trigger specific histone modifications resulting in apoptotic gene silencing during HCC. Thus, we propose to test the hypothesis that epigenetically-induced deregulation of the apoptotic pathway promotes transformation to malignancy. To conclude, although the deregulation of the apoptotic machinery in carcinogenesis is well established, there is a gap in our understanding as to how apoptotic genes are involved and how is their expression regulated in malignancy. Our proposal fills in the gaps in linking the epigenetically-induced alterations in apoptotic gene expression to the defective apoptotic phenotype characteristic of HCC. Furthermore, our proposal elucidates the molecular mechanisms by which specific histone modifications converse with the DNA methylation machinery in order to silence specific apoptotic genes. Finally, determining the molecular identity of these epigenetic modifications is of paramount importance because such information can be utilized in designing more efficient cancer therapeutic strategies based on the concept of selective apoptotic activation in malignant cells thus making such strategies more efficient and less cytotoxic.