Some virus-related cancers harbor a unique type of somatic mutation, namely viral DNA insertions, in the genomes. In carcinogenic retroviruses in animals, viral provirus integrations select cells with insertion at sites which activate downstream oncogenes. In HBV-related liver cancers, about 90% of them contain integrated HBV DNAs in the genomes, suggesting an intriguing possibility for carcinogenesis. Recent studies identified the hotspots of such integrations which may activate cellular genes in promoting carcinogenesis. The HBV DNA integrations analysis also may provide a useful classification of HCC. Finally, the HBV DNA integrations are harnessed as a signature cell-free circulating tumor DNA for detecting minimal residual diseases during or after therapy.