The hepatitis B virus (HBV) is one of the leading causes of hepatocellular carcinoma (HCC) worldwide. In the endemic region, the infection is commonly spread through vertical transmission in which mother and child possess genetically identical viral genotypes in the setting of similar host genomes. Despite these genetic similarities, clinical outcomes from chronic hepatitis B (CHB) can vary widely, ranging from lifelong asymptomatic infection to terminal HCC. Presented here are the longitudinal observations over multiple decades of three family clusters, including monozygotic twins with non-discordant HCC, that demonstrate the heterogeneity of HBV-related outcomes. These findings emphasize the important need to untangle the role of genetic and non-genetic host factors in the development of HBV-related HCC, as well as highlight the novel research avenues that can clarify the contributions of such factors in HBV-related HCC.