Abstract: The active replication phases of the hepatitis B virus (HBV) are marked by a high frequency of mutational events resulting from an enormous daily viral turnover rate and an error-prone polymerase. Because HBV is not directly cytopathic, it is the host's immune response that accounts for most of the liver disease associated with persistent infection. HBV escape mutants can be found at the transitional phases of chronic hepatitis B, such as hepatitis B e antigen (HBeAg)-positive versus HBeAg-negative infection, and these mutants are selected out from the diverse quasispecies pool comprising the HBV population at that time. Not surprisingly, the introduction of nucleoside and nucleotide analog therapy has also seen the emergence of drug resistance, which has become the major factor limiting the long-term application of antiviral agents for patients with chronic hepatitis B. Thus, the prevention of resistance requires the adoption of strategies that effectively control virus replication and exploit a detailed understanding of the mechanisms and processes that drive the emergence of drug resistance.