Hepatitis B virus (HBV) infection is associated with chronic liver diseases (CLD), which progress from hepatitis to fibrosis, cirrhosis, and finally hepatocellular carcinoma (HCC) over 30-50 years. The pathogenesis of CLD is immune mediated, which is characterized by persistent immune responses against virus infected hepatocytes. During bouts of CLD, the virus gene encoding the hepatitis B x antigen (HBx) is increasingly found integrated at multiple sites within the human genome. Many of these integrated templates express HBx, which is a trans-regulatory protein that supports virus gene expression and replication on one hand, but also alters patterns of gene expression in the infected cell. HBx alters gene expression by constitutively activating signal transduction pathways in the cytoplasm and promoting epigenetic mediated changes in the expression of cellular genes. In doing so, HBx contributes to the persistence of virus infected cells and to the pathogenesis of CLD by triggering multiple hallmarks which are characteristic of cancer.