Hepatitis B virus (HBV) infection has always been one of the most important public health issues in mainland China, causing a huge disease burden. It often takes decades for the chronic process of malignant transformation from HBV infection to different stages of liver diseases. Mutations associated with virus survival are eventually selected by the chronic infection process and under the immune pressure of host. These selected HBV mutations further promote the malignant transformation of liver diseases. A large amount of somatic mutations are produced in the HBV-related chronic inflammatory micro-environment, and those survival-related mutations will then be selected. The selected HBV mutations and host somatic mutations work together to promote the malignant transformation, which can be termed as an evolutionary process of "mutation-selection-adaptation". In addition, genetic variations of individual hosts also play an important role in HBV related disease progression. For example, single-nucleotide polymorphisms of STAT pathway and HLA can interact with important HBV mutations and therefore affect HBV-related disease progression.