Treatment of chronic hepatitis B has improved substantially over the past five years. Pegylated interferon alpha2a and entecavir have been approved by the FDA and joined the armamentarium of therapies that includes inteferon alpha (IFN-alpha), lamivudine, and adefovir dipivoxil. Several key questions come to mind regarding treatment. Who should receive treatment? Which agent should they be given? How long should treatment last? Treatment is indicated for patients with a high pretreatment alanine aminotransferase level, detectable HBV DNA, and active inflammation on liver biopsy. When selecting an agent, the likelihood of achieving a sustained response should be weighed against long-term risks. IFN-alpha, lamivudine, and adefovir dipivoxil are equally efficacious; however, even though IFN-alpha and pegylated IFN-alpha have a durable response, both are associated with unpleasant side effects. Long-term lamivudine therapy has a high rate of drug resistance compared with adefovir dipivoxil, which has a low rate of drug resistance and a small risk of reversible nephrotoxicity. Entecavir reduces HBV load more effectively than the other therapies, but it is associated with increased drug resistance in patients with lamivudine-resistant HBV. The key to therapy seems to be some combination of therapies--both existing and those in development--that has yet to be determined.