Lamivudine and adefovir have potent inhibitory effects on hepatitis B virus (HBV) replication. Although short-term therapy is feasible in a selected subgroup of patients, prolonged therapy is required for sustained suppression in the majority of patients. However, HBV species with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV RNA-dependent DNA polymerase (rtM204 I/V) conferring resistance to lamivudine may emerge after 9-10 months therapy. The incidence increases with duration of therapy up to 70% after 5 years lamivudine therapy. Serum alanine aminotransferase (ALT) elevation and HBV DNA rebound ( I log) occur in >90% of the patients with rtM204 I/V during continued lamivudine therapy. Marked flare of serum ALT may occur, sometimes severe, and may be complicated with decompensation or even fatality. The initial clinical and histologic improvement may also reverse after emergence of rtM204 IN Studies do suggest that stopping seems better than continuing lamivudine therapy. Limited data show that interferon therapy seems ineffective. Add-on adefovir therapy is effective in suppressing rtM204 I/V in both compensated and decompensated patients. Switching to adefovir monotherapy is effective and safe even in cirrhotic patients with decompensation. The overall incidence of adefovirresistant rtN236T and A181V is low, being 0 after one year and 5.9% after 3 years' therapy. The impact of adefovir resistance is less clear but is responsive to lamivudine therapy. In conclusion, monitoring of viral breakthrough to start effective intervention is mandatory during direct antiviral therapy.