Heredity and variability are fundamental characteristics of living organisms, and viruses are no exception. One very important characteristic of hepatitis B viruses is that they are highly variable, and the hepatitis B viruses in any one patient are groups of viruses whose genetic sequences or amino acid sequences (the ordering of different nucleotides and amino acids) are not identical; in other words, there are no identical hepatitis B viruses in a patient, including viruses that are resistant to or ineffective in treatment with direct antiviral drugs (currently only nucleoside or nucleotide analogues are in clinical use). In other words, there are no identical hepatitis B viruses in a patient’s body, including viruses that are resistant to or ineffective in treatment with direct antivirals (currently only nucleoside or nucleotide antivirals are in clinical use). Prior to treatment with antivirals, viruses that are resistant to direct antivirals have relatively low replication or multiplication capacity and therefore do not predominate. After the administration of direct antivirals, viruses sensitive to or effective in treatment with direct antivirals are suppressed, while viruses resistant to or ineffective in treatment with direct antivirals progressively predominate. Viruses resistant to direct antivirals select for viruses with enhanced replication capacity that are resistant to direct antivirals by further mutation during ongoing replication. If the virus resistant to direct antiviral drugs changes from low replication to high replication, treatment ineffectiveness and hepatitis reactivation occur, which is called drug resistance. The emergence of viral resistance during antiviral therapy is an inevitable phenomenon, and the continued effectiveness of antiviral therapy can only be ensured through regular follow-up and early detection with timely interventions. Preventive measures include: avoiding cardiac and physical overload, taking medication regularly and quantitatively according to the instructions, following up and checking on time according to the doctor’s recommendations, etc.; methods to deal with drug resistance include: combining with other direct antiviral drugs with no crossover in gene sequence or amino acid sequence variant sites, combining with thymidine based immunostabilizing agents, combining with interferon based indirect antiviral drugs, stopping direct antiviral drugs under the doctor’s guidance etc. It is important to point out that establishing the view that antiviral therapy is effective for a limited period of time, consciously following the doctor’s advice and accepting the doctor’s supervision are the basic principles of prevention and management of drug resistance.