Several agents are currently approved for the treatment of chronic hepatitis B: interferon alpha (IFN), pegylated interferon-α (PEG IFN), lamivudine, adefovir, and entecavir. Each agent has inherent limitations. IFN is effective in a minority of patients and has frequent side effects that limit its tolerability. Large randomized controlled trials have demonstrated the efficacy of PEG IFN in the treatment of chronic hepatitis B. The efficacy of lamivudine is limited by the emergence of drug-resistant hepatitis B virus (HBV) mutants, restricting its utility as a long-term therapy. Adefovir is well tolerated and is associated with low incidence of resistance, but its antiviral effect is not optimal. Entecavir has a high antiviral effect and is well tolerated. However, its long term efficacy and resistance profile are not yet determined. Lamivudine, adefovir and entecavir have the advantages of oral administration and excellent safety profiles. However, theyinduce a sustained response after withdrawal of therapy in only a minority of patients, and therefore, the treatment needs to be indefinitely administered in most patients. IFNs have two mechanisms of action: (i) direct antiviral effect by inhibiting synthesis of viral DNA and by activating antiviral enzymes; and (ii) exaggeration of the cellular immune response against hepatocytes infected with HBV. PEG IFN, administered for 48 weeks, gives an overall sustained response rate of approximately 30%. Two large randomized controlled trials have conducted to registration of PEG IFN-α-2a in the treatment of chronic hepatitis B.