Primary liver cancer is one of the most common cancers at the global level, accounting for half of all cancersin some undeveloped countries. This disease tends to occur in livers damaged through alcohol abuse, or chronicinfection with hepatitis B and C, on a background of cirrhosis. Various cancer-causing substances are associatedwith primary liver cancer, including certain pesticides and such chemicals as vinyl chloride and arsenic. Thestrong association between HBV infection and liver cancer is well documented in epidemiological studies. It isgenerally acknowledged that the virus is involved through long term chronic infection, frequently associatedwith cirrhosis, suggesting a nonspecific mechanism triggered by the immune response. Chronic inflammation ofliver, continuous cell death, abnormal cell growth, would increase the occurrence rate of genetic alterations andrisk of disease. However, the statistics indicated that only about one fifth of HBV carries would develop HCCin lifetime, suggesting that individual variation in genome would also influence the susceptibility of HCC. Thegoal of this review is to highlight present level of knowledge on the role of viral infection and genetic variationin the development of liver cancer.