Over the past 10 years, an increasing number of mutations in the hepatitis B virus genome have been described. While the majority of these mutations appear to be ‘silent’ or not clinically relevant, some have been described in association with increased severity of disease (core and basic core promoter mutations), evasion of immunological surveillance (S escape mutants), hepatocellular carcinogenesis (X mutants) and resistance to antiviral agents (DNA polymerase mutations). The molecular events and the clinical consequences thereof are reviewed.