Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B evolves in the natural history of chronic hepatitis B virus (HBV) infection linked with selection of nonproducing HBeAg but replication-competent HBV mutants, and may have a potentially severe and progressive course. Effective suppression of HBV replication is the main therapeutic target. Sustained off-therapy responses are rare with treatment of finite duration, except perhaps for interferon-based therapies, which induce such responses in a sizeable, yet small proportion of patients. Eventually, the majority of patients will be treated with long-term oral antiviral therapy, which improves patients' outcome but is associated with progressively increasing rates of viral resistance. The long-term resistance profile of adefovir is significantly better than that of lamivudine (LMV), whereas data for entecavir currently are limited to 2 years, with resistance developing in LMV-resistant but not in treatment-naïve patients. Combination therapy with adefovir added to LMV in LMV-resistant patients is extremely effective; cases of adefovir-resistance have not been reported to date.