The clinical sequelae of chronic hepatitis B (CHB), such as liver cirrhosis and hepatocellular carcinoma, are determined mainly by the host immune response to the hepatitis B virus-encoded antigens. Disease remission in CHB has been associated with sustained viral suppression < 104 to 105 copies/mL. This can be achieved by either restoring the host immune control on the virus with immunomodulatory therapy, such as conventional or pegylated interferon-alfa therapy, or by continuous suppression of the viral replication by nucleos(t)ide therapy, such as lamivudine, adefovir dipivoxil, or entecavir treatment. Given that not all patients can tolerate or will respond to interferon-alfa-based therapy, maintenance therapy with nucleos(t)ide therapy is the alternative. However, this latter approach can lead to development of viral resistance and long-term safety concerns. Further improvement in CHB therapy is limited by a lack of understanding of the host immune characteristics associated with sustained disease remission.