Patients with chronic hepatitis B who are treated with oral antivirals are always concerned about drug resistance. This concern is indeed not unreasonable, as drug resistance is an extremely important issue in the treatment of chronic hepatitis B with nucleoside analogues. Compared with patients without drug resistance, drug resistance not only leads to further disease progression and increases the risk of liver failure and hepatocellular carcinoma; it also makes follow-up treatment more difficult and increases the medical cost of long-term treatment. From a mechanistic point of view, nucleoside resistance is almost inevitable, as it is a series of adaptive mutations that occur in the virus to escape drug pressure. There are four nucleoside analogues most commonly used in China for the treatment of chronic hepatitis B: lamivudine, adefovir, telbivudine and entecavir. These drugs have varying degrees of resistance. According to available clinical trial data, for primary chronic hepatitis B, lamivudine has a resistance rate of 24% for 1 year of treatment and up to 70% for 5 years of treatment. For 2 years of treatment with tebivudine, the resistance rates were 25% and 11% in HBeAg-positive and negative patients, respectively. The cumulative resistance rates for HBeAg-positive and -negative patients at 5 years of treatment with adefovir were 42% and 29%, respectively. Entecavir has a lower resistance rate, with a 3-year resistance rate of about 1.5%. In China, the drug resistance problem is more serious, which is mainly caused by irregular treatment, including random drug changes and frequent drug additions. Usually, the first manifestation of drug resistance is a virological breakthrough, followed by a biochemical breakthrough, which means that HBV DNA, which has already turned negative, rises again, and transaminases, which have been normalized, rise again. However, it is important to note that not all virological breakthroughs are caused by drug resistance, so drug resistance testing should be done to confirm the diagnosis if drug resistance is detected. Viral genotype mutations occur several months earlier than biochemical breakthroughs, so early detection of drug resistance and prompt management can prevent hepatitis flare-ups. In patients with good compliance, once a viral elevation is detected, the patient should be immediately tested for compliance problems and the virus should be retested in 1 month, and genotypic resistance testing can be performed if available. When drug resistance is detected or virologic breakthrough is confirmed, salvage therapy should be given immediately. The treatment option for drug resistance is to add antivirals without cross-resistance (see the table below for specific options) to minimize the risk of multidrug resistance. Alternatively, pegylated interferon therapy may be considered for drug-resistant patients. Antiviral resistance salvage therapy Patients need to be aware that although salvage therapy can better inhibit replication of resistant strains, it also carries an increased risk of multidrug resistance. Therefore, to solve the problem of drug resistance, it is more important to choose carefully during the initial treatment. Priority may be given to limited courses of pegylated interferon therapy, and if nucleoside therapy is chosen, highly effective, low resistance nucleosides should be chosen as much as possible.