Three hundred and fifty million people worldwide are estimated to be chronically infected with hepatitis B virus. 15-40% of these subjects will develop cirrhosis, liver failure or hepatocellular carcinoma during their life. The treatment of chronic hepatitis B has improved dramatically over the last decade thanks to the advent of nucleoside/ nucleotide analogues and the use of pegylated interferons. However, these agents have increased the complexity of the management of hepatitis B. Five drugs have been approved for chronic hepatitis B treatment: standard interferon-α2b, pegylated interferon-α2a, lamivudine, adefovir dipivoxil, and entecavir. A definite course of standard or pegylated interferon is administered to induce hepatitis B virus clearance. Unfortunately, these agents are not effective in all patients and are associated with not negligible side effects. Nucleoside or nucleotide analogues that inhibit hepatitis B virus polymerase induce on-treatment suppression of viral replication but patients tend to relapse after cessation of treatment. Consequently, these analogues, which are well tolerated, should be used for prolonged periods, even indefinitely. However, prolonged treatment is associated with a high rate of resistance. The following anti-hepatitis B virus drugs are currently undergoing clinical testing: telbivudine, emtricitabine, tenofovir disoproxil fumarate, clevudine and thymosin-α1. Here we will examine the mechanism of action, efficacy, safety, tolerability and emergence of resistance of agents used to treat chronic hepatitis B. We shall also examine the potential of drugs now being tested and of combination treatment.