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Chronic hepatitis B (CHB) remains a major public health problem worldwide. In the early 1980's patients from the Mediterranean area, although negative for HBeAg and positive for antibodies to HBeAg (anti-HBe), were reported to have CHB with replicating hepatitis B virus (HBV). The typical course of HBeAg-negative CHB was characterized by an intermittent pattern of disease activity with elevations of alanine aminotransferase (ALT) values preceded, in most instances, by increase in HBV-DNA levels. The response to interferon (IFN) treatment in HBeAg-negative CHB is disappointing. The diagnosis of CHB is based on HBsAg positivity for more than six months associated with HBV replication documented by either HBeAg positivity and/or HBV-DNA in the serum, and increased ALT levels, either persistent or intermittent. The main strategies to combat chronic HBV infection rely on the stimulation of the specific antiviral immune response and on the inhibition of viral replication. The IFN therapy is only moderately effective and often limited by dose-dependent side effects. Recently, new nucleoside analogues, such as lamivudine, have shown very promising results in terms of antiviral effect and tolerance. The prolonged administration of lamivudine is most often associated with a control of viral replication rather than eradication, and may select for resistant mutants. The search for new antiviral agents is therefore mandatory to design combination strategies.