One of the concerns many people have when taking oral antiviral drugs is drug resistance. So, what is drug resistance all about? Why does drug resistance occur? HBV is a hepatophilic DNA virus with a 3.2 kb long genome and a partially double-stranded circular DNA structure. HBV genome contains four partially overlapping open reading frames, namely the pre-S/S region, pre-C/C region, P region and X region. The P region encodes a polymerase/reverse transcriptase that is the site of action of nucleoside and nucleotide analogues (NUCs), widely used antiviral drugs, and the HBV drug resistance mutations triggered by NUCs are all located in the P region of the HBV genome. HBV has a high replication efficiency, producing 1012-13 viral particles per day, which is 10-fold higher than HCV and 100-fold higher than HIV. Since HBV replicates by reverse transcription of pregenomic RNA intermediates into negative-stranded DNA, and this reverse transcription process is carried out using the virus’ own DNA polymerase, this enzyme lacks proofreading activity and is prone to base pairing errors. One mismatch occurs for every 105 nucleosides in a replication cycle, so that 1010-11 mismatches occur per day, and with the HBV genome being only about 3.2 kb, any kind of base change can occur at each site every day. Viral quasispecies (quasispecies) are dynamic populations of highly related but not identical mutant strains and recombinant genomes affected by genetic mutations, competition, and selection.HBV replicates at high levels and is prone to base pairing errors due to the lack of proofreading activity of DNA polymerase during HBV replication, so mutations are generated quite rapidly. The cluster of related mutant strains of viruses formed in HBV-infected patients with one dominant strain is generally referred to as HBV quasispecies. The increasing number of HBV-induced resistance mutations (especially multidrug resistance mutations and cross-resistance mutations) triggered by NUCs HBV persistent replication and liver inflammatory response necrosis are the determinants of disease progression. However, with the widespread use and irregular application of NUCs (including single-drug random sequences, frequent drug changes or drug additions within a short period of time, and unreasonable drug additions or drug changes after drug resistance), the generation of HBV drug-resistant mutations cannot be completely avoided and is gradually increasing, and has become an important factor limiting the treatment of HBV-related liver diseases. The development of HBV drug-resistant mutations cannot be completely avoided and is gradually increasing, and has become an important factor limiting the treatment of HBV-related liver diseases. NUCs are the most widely used anti-HBV drugs in clinical practice, and these drugs are divided into three major categories: 1. L-type nucleoside analogues including lamivudine (LAM), telbivudine (LdT), emtricitabine and clavulanic acid; 2. acyclic phosphates including adefovir (ADV) and tenofovir (TDF); 3. D-type cyclopentane (alkene) drugs, which include deoxyguanosine analogs, entecavir (ETV). Currently, the American Academy of Liver Diseases (AASLD), the European Academy of Liver Diseases (EASL) and the Asia Pacific Society of Liver Diseases (APASL) have adopted potent and low resistance ETV and TDF as first-line antiviral drugs. In China, however, due to geographical differences and uneven economic development, LAM and ADV are still widely used as initial therapy, especially the domestically produced ADV; when LAM or ADV shows poor response or clinical resistance, it is again a simple sequential dosing. Meanwhile, poor patient compliance is one of the important reasons for the consequent increase in the resistance rate of NUCs. Therefore, the increasing number of refractory drug-resistant strains, multidrug-resistant strains and cross-resistant strains triggered by NUCs has become a serious global public health problem limiting the prevention and treatment of diseases associated with chronic HBV infection.