Despite a high rate of viral clearance by immunocompetent adults, and the availability of efficient vaccines a large proportion of the world’s population (400 million) is chronically infected with hepatitis B virus (HBV). This is due to the fact that vertical transmission of HBV in neonates leads to a chronic infection in 90% of cases. The pathology is immune-mediated. The coexistence of repeated cycles of HBV replication and immune lysis of infected hepatocytes is associated with fibrosis, cirrhosis, and hepatocellular carcinoma. There are still 250 000 deaths each year resulting from hepatitis B. Current strategies for treating hepatitis B have focused on clearance of active HBV infection through suppression of viral replication. The efficacies of these treatments have been determined by monitoring the levels of HBV DNA in serum, serum alanine aminotransferase (ALT) levels, loss of viral antigens (HBeAg and HBsAg), seroconversion (antiHBe and anti-HBs), and ultimately by improvements in liver histology. Interferon-a (IFN-a) and the nucleoside analogs (lamivudine and adefovir) have proven their effectiveness by these clinical markers and are currently approved for treatment of chronic hepatitis B. Sustained virological response rate, however, ranges between 15 and 40% [1]. The actual rate of sustained response in non selected patients is supposed to be lower. Following the introduction of IFN acting mainly through immune potentiation, the development of new antivirals that inhibit the viral polymerase has provided new hope in the therapy of chronic hepatitis B. However, due to the slow kinetics of viral clearance, longterm treatment is mandatory and unfortunately, the spontaneous genetic heterogeneity of the virus prompted drug resistant mutants selected by the treatment. It is, therefore, similar to human immunodeficiency virus (HIV), critical to develop new antiviral strategies to better combat wild-type and mutant HBV infections.