To ensure that long-term antiviral therapy is effective, it is important to be on the lookout for drug resistance. As the old saying goes, “prevention is better than cure”, and drug resistance is all about prevention. How to prevent drug resistance? First, we should consistently tighten the string of drug resistance prevention, and the awareness of drug resistance prevention should be carried out throughout the antiviral treatment; second, two points should be grasped for drug resistance prevention: 1, try to stimulate and maintain the immunity of oneself to clear and control hepatitis B virus; 2, preferred potent and low-resistance drugs such as entecavir or tenofovir. Third, the patient antiviral, doctors often think three times: First, the patient has its own clearance of hepatitis B virus, and gradually their own recovery is possible? Secondly, can the patient control the replication of hepatitis B virus safely, effectively and permanently by injecting interferon? Third, must the patient start longer-term oral antiviral medication immediately? Does the disease allow for further observation? In 1999, lamivudine was launched on the market, and mankind had a new weapon in the fight against hepatitis B. We entered a new era of nucleoside analogs for the treatment of hepatitis B, and the monster of drug resistance came along with lamivudine. We now have five nucleoside (acid) analogs, as long as doctors and patients work together, doctors standardize antiviral treatment in accordance with China’s hepatitis B guidelines, and patients conscientiously carry out the doctor’s instructions, we will certainly be able to drug-resistant monster into the iron cage of standardized treatment, and can no longer endanger hepatitis B patients.