Liver cancer represents a significant cancer burden worldwide, especially in developing countries. Liver cancer is often only diagnosed at a late stage and has a high mortality rate, which underscores the importance of early diagnosis and treatment. Hepatocellular carcinoma (HCC) is the major histopathological type of liver cancer. Chronic infection with hepatitis B virus (HBV) is a well-established risk factor for HCC. HBV sequence variation may influence the outcome of HBV infection and the development of HCC, with at least ten HBV genotypes (A to J) identified to date. Several HBV genotypes and mutations in pre-S and pre-core/core promoter regions are closely associated with HCC pathogenesis, and are considered predictive biomarkers of HCC. Yet, only a small fraction of chronic hepatitis B patients develop HCC, and some HCC cases are diagnosed with no known predisposing risk factors, suggesting a potentially important role for host genetic variation in HCC carcinogenesis. In this review, we summarize the current findings on HBV genotypes and mutations, host genetic variations, and their interactions involved in HCC carcinogenesis. Understanding key viral and host genetic variation is essential for generating effective predictive biomarkers of HCC.