Aflatoxin B1 (AFB1) is classified as a group I carcinogen in humans by IARC. However, the exact mechanisms of AFB1 hepatocarcinogenesis have not been fully elucidated. Recent studies have suggested that oncogenes are critical molecular targets for AFB1, and AFB1 causes characteristic genetic changes in the p53 tumor suppressor gene and ras protooncogenes. Up to date, more than 1500 human hepatocellular carcinoma (HCC) samples have been examined for p53 mutations with respect to different AFB1 exposure levels. The most significant finding is that more than 50% of HCC patients from high aflatoxin exposure areas such as southern Africa and Qidong, China harboured a codon 249 G to T transversion in the p53 tumor suppressor gene, which is found to be consistent with the mutagenic specificity of AFB1 observed in vitro. In contrast, this mutational pattern is not found in HCC samples from moderate or low aflatoxin exposure countries or regions. Therefore, this hot-spot mutation is believed to be a molecular fingerprint linking the initial event of AFB1-DNA adduct formation with the ultimate development and progress of human HCC. However, some important points still remain to be explicated. First, in many of these studies, the systematic evaluation of AFB1 exposure is rather limited and the classification of AFB1 exposure level is speculative and confusing, without the definite evidence for the actual aflatoxin exposure level. Second, the role of hepadnaviral infection has to be considered in the induction of this unique mutational spectrum. On the other hand, ras oncogene mutations are frequently found in AFB1-induced HCC samples in experimental animals, while the frequency of ras mutation in human HCC in contrast is much lower than that of p53. Recent studies have provided additional evidence that reactive oxygen species (ROS) and oxidative DNA damage may be involved in AFB1-induced p53 and ras mutations. In future, follow-up cohorts exposed to different levels of AFB1 combined with the determination of putative gene markers are much needed.