Current monotherapy with interferon (IFN), lamivudine, or adefovir remains unsatisfactory for most patients with chronic hepatitis B infection. Prolonged treatment with lamivudine monotherapy is needed in most patients with chronic hepatitis B infection and leads to an increased risk of developing lamivudine resistance. Recent data suggest that lamivudine resistance occasionally can result in serious clinical sequelae. On the other hand, conventional IFN treatment is ineffective in up to 70% of chronic hepatitis B patients. Adefovir resistance, although less frequent than lamivudine resistance, also has been identified. With the introduction of new nucleoside/nucleotide analogs such as entacavir, clevudine, L-Fd4C, tenofovir, and immunomodulatory agents such as pegylated IFN, new treatment options, either alone or in combination, are being investigated to increase the response rate in treatment-naive and treatment-experienced chronic hepatitis B patients.