Treatment of Chronic Hepatitis B has changed in the last few years with the introduction of oral antivirals (lamivudine, adefovir, entecavir, telbivudine and tenofovir) that together with interferón (standard and pegylated) constitute the therapeutic arsenal. All of these has permitted to increase the therapy indications allowing to treat patients with advance liver disease and decompensate liver disease. The main limitation of oral antivirals is the emergence of HBV strains drug resistance. The challenge are to prevent the emergence of HBV drug resistance and to achieve complete and persistent HBV replication in order to avoid the progression of the liver disease and the development of HBV related complications.