Chronic hepatitis B virus (HBV) infection remains a major public health problem worldwide. Until recently, interferon (IFN)-alpha was the only approved drug for the treatment of chronic HBV infection. The recent registration of lamivudine, a dideoxycytidine analogue that inhibits both the HIV and HBV reverse transcriptases, has provided new perspectives for the treatment of chronic HBV infection. Lamivudine treatment for 12 months leads to a control of viral replication during therapy in the majority of the patients and to sustained anti-hepatitis B e (anti-HBe) seroconversion in 16 to 22% of the patients, associated with a biochemical and histological response. Further studies showed that extended lamivudine therapy increases the rate of anti-HBe seroconversion. However, long-term therapy is associated with the progressive emergence of drug resistant mutants. In most cases these mutants are not associated with a deterioration of the liver disease within the available follow-up. In the remaining patients and in particular settings such as liver transplantation, a severe exacerbation of the liver disease is observed and that requires add-on therapy. Lamivudine treatment of patients infected with a pre-core mutant also showed beneficial effect with the control of viral replication, and a biochemical and histological response in approximately 60% of the patients at 1 year. These patients face the same problem of drug resistant mutants, and the optimal duration of lamivudine treatment still needs to be determined in this clinical situation. Moreover, lamivudine therapy is the only therapeutic option in decompensated cirrhotic patients to allow liver transplantation, and in liver transplant patients with HBV recurrence following transplantation. Adverse effects of lamivudine therapy are comparable to those observed in placebo-treated patients. ALT flares have been observed mainly in relation to the re-occurrence of viral replication due to the rebound of viral replication after therapy withdrawal, or to the emergence of drug resistance mutants. Therefore, lamivudine provides a new treatment alternative for patients with chronic HBV infection. For each patient, its indication has to be weighed against the risk of developing viral resistance but also against the risk of natural history of the disease.