The universal HBV vaccination programme in Taiwan has effectively led to the reduction of acute and chronic hepatitis B, and of hepatocellular carcinoma among vaccinated children. Seropositivity rates for hepatitis B surface antigen (HBsAg) decreased from 10-17% in those born before the start of the vaccination programme to the current 0.5-1.7%. Nonetheless, breakthrough infection continues to be observed. The main causes include high maternal viral load, intrauterine infection, emergence of S gene mutants and immunosuppression. Among vaccinated individuals with breakthrough HBV infection, sG145R & sT126A/S mutations (which account for 48% of the mutants detected) have become prominent. However, owing to the marked reduction in the HBsAg carrier rate, the prevalence rate of S gene mutants in the total vaccinated population has not increased. With limited evidence of spread, S gene mutants do not need to be incorporated into the HBV vaccine. Further studies are required to design better strategies to prevent breakthrough HBV infection of both wild-type and S gene mutants.