Hepatitis B virus (HBV) infection is a global health issue. Effective and individualized treatment of chronic hepatitis B to prevent progression to end-stage liver diseases and hepatocellular carcinoma is needed. HBV can be classified into eight genotypes (A-H) on the basis of genome sequence divergence. In addition, several naturally occurring HBV mutants have also been identified. The epidemiology of HBV genotypes and their implications for response to antiviral therapy have become increasingly recognized. Recent studies suggested that responses to standard interferon treatment in patients with genotype A or B are better than those with genotype C or D; however, conflicting results exist regarding the response to pegylated interferon. The influence of dose and duration on interferon-based therapy remains to be clarified. In addition to genotype, naturally occurring mutations such as precore and core promoter mutations have also attracted much attention, because they have been shown to affect the disease progression of HBV-related chronic liver disease and possibly the response to antiviral therapy. Here, we review the differences in antiviral theraputic response among HBV genotypes and discuss the role of precore or core promoter mutations in response to antiviral therapy.