The goals of therapy in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) are to abolish or efficiently suppress viral replication, which represents the main determinant of underlying liver necroinflammation and fibrosis. Currently available agents include interferon-alfa (IFN-alpha), lamivudine, and soon adefovir dipivoxil. A > or = 12-month course of IFN-alpha treatment or retreatment achieves sustained biochemical responses in 15 to 25% of patients with eventual hepatitis B surface antigen (HBsAg) loss and anti-HBs development in a proportion of them. Lamivudine induces initial virologic and biochemical responses in 70 to 90%, but breakthroughs due to lamivudine-resistant mutants accumulate with continuation of therapy and thus only one third of patients may remain in remission after the third year of therapy. Adefovir dipivoxil also achieves on-therapy responses in the majority of cases. Adefovir dipivoxil and entecavir appear to be effective against lamivudine-resistant strains. Many other antiviral agents and immunomodulatory approaches are currently evaluated for CHB, but, besides IFN-alpha, none has yet been convincingly shown to induce sustained off-therapy responses.