Hepatitis B virus infection can lead to a series of liver diseases, including acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Among the commonly used antiviral drugs, nucleoside analogs are widely used in clinical practice because of their potent viral inhibition and low toxic side effects. However, with the prolongation of drug use, the problem of nucleoside analog resistance has become more and more prominent. According to the available clinical trial data, lamivudine treatment of primary chronic hepatitis B patients, 1-year drug resistance rate of 24%, 5-year drug resistance rate of up to 70%. Tebivudine treatment of HBeAg-positive chronic hepatitis B, 2-year drug resistance rate of 25%. Even with entecavir, the resistance rate is still 1.7% at 3 years of treatment. What is drug resistance and why is the hepatitis B virus “resistant” to nucleosides? This involves molecular virology, which is not easy to understand. Simply put, the hepatitis B virus is a long chain of deoxyribonucleotides that replicate with the help of polymerase enzymes. Nucleoside drugs block the action of this enzyme and thus inhibit viral replication. When the drug is first taken, the nucleoside analogs work well, but under the pressure of this drug, the virus gradually mutates to escape the effect of the drug on the polymerase enzyme, i.e., a drug-resistant mutation occurs. Drug resistance means that a particular nucleoside analog is no longer effective against the virus, and once resistance occurs the virus that had declined or turned negative will rebound and increase, which can also lead to disease progression. Moreover, resistance to a nucleoside does not just reduce the number of drugs available, but also implicates a number of other nucleosides. For example, once lamivudine resistance, similar tibivudine and will also be resistant, which is what doctors call cross-resistance; and this is not only the same type of drug will be cross-resistant, for different classes of drugs, such as adefovir, entecavir, the incidence of drug resistance will also increase. Obviously, the drug resistance problem for nucleoside analogs is difficult to avoid and the harm is serious. At present, with the increased application of nucleoside analogs in our country, the drug resistance problem of antiviral therapy for chronic hepatitis B cannot be ignored. In order to actively deal with this problem, firstly, in the initial treatment, interferon therapy should be given priority to patients who are suitable for interferon therapy, in order to achieve therapeutic success through a limited course of treatment, and to avoid the problem of drug resistance at the source; secondly, patients who have received nucleoside analogues should be closely monitored, and once drug resistance occurs, they should be reasonably added to the medication or change the medication, so as to avoid the emergence of cross-resistance, multidrug resistance, which makes the follow-up program more complicated and difficult. The emergence of multi-drug resistance makes the follow-up program more complicated and difficult.