Hepatitis B virus(HBV) circulates in blood and replicates in the presence of quasispecies. During HBV replication, HBV DNA polymerase lacks fidelity and proofreading function partly because its exonuclease activity is either absent or deficient. Therefore, HBV genome is mutated with unusually high frequency. And these mutations can affect more than one open reading frame due to overlapping genes. Otherwise, natural substitutions, deletions or insertions involving the Cp/ENⅡ locus in the X gene can significantly alter the extent of viral replication activity. Particular selection pressures such as host immune system and antiviral therapy readily select out escape mutants from this pre-existing quasispecies pool. Antiviral drug resistance in chronic hepatitis B(CHB) can be caused by the viral mutation frequency, the intrinsic mutability of the antiviral target site, the selective pressure exerted by the drug, the magnitude and rate of virus replication, the overall replication fitness of the mutant, the genetic barrier of the compound and the availability of replication space. Potent inhibition of HBV replication could be able to prevent the development of drug resistance because mutagenesis is replication dependent. Viral load may decline to a point where the continued production of quasispecies with the potential to resist new drug treatments no longer occurs, if viral replication can be suppressed for a sufficient length of time. HBV DNA, HBV DNA polymerase lacks fidelity and proofreading function due to its exonuclease activity is either absent or deficient. Thus, HBV genome is mutated with unusually high frequency . And these mutations can affect more than one open reading frame due to overlapping genes. Otherwise, natural substitutions, deletions or insertions involving the Cp / ENⅡ locus in the X gene can significantly alter the extent of viral replication activity. host immune system and antiviral therapy readily select out escape mutants from this pre-existing quasispecies pool. Antiviral drug resistance in chronic hepatitis B (CHB) can be caused by the viral mutation frequency, the intrinsic mutability of the antiviral target site, the selective pressure exerted by the drug, the magnitude and rate of virus replication, the overall replication fitness of the mutant, the genetic barrier of the compound and the availability of replication space. Potent inhibition of HBV replication could be able to prevent the development of drug resistance because mutagenesis is replication dependent. Viral load may decline to a point where the continued production of quasispecies with the potential to resist new drug treatments no longer occurs, if viral replication can be suppressed for a sufficient length of time.