Abstract: Long- term antiviral therapy with nucleos( t) ide analogues against hepatitis B virus may lead to the occurrence of drug- resistant viral mutations. As a challenging topic in antiviral research,the problem of drug- resistant mutations may be associated with the aggregation of chronic hepatitis B and the development of primary hepatic carcinoma. In- depth understanding of the evolution characteristics of drug-resistant mutants during long- term antiviral therapy will allow a selection of appropriate clinical drug resistance monitoring approach. Within the time interval between the occurrence of genotypic resistance and virological breakthrough,dynamic monitoring of variations in the proportion of drug- resistant variants in the quasispecies pool and timely change of the therapeutic regimen will help to optimize the treatment of chronic hepatitis B and develop effective antiviral drugs.