Despite the development of new therapeutic options, treatment of chronic hepatitis B remains a clinical challenge because of the need for long-term treatment in most patients. Treatment with pegylated interferon is the only option that allows a defined duration of treatment. Nonetheless, approximately 70% of the patients treated do not have a prolonged treatment response. A variety of nucleoside analog viral polymerase (reverse transcriptase) inhibitors have been developed (lamivudine, adefovir dipivoxil, entecavir, telbivudine); they can be administered orally and are well tolerated. These antiviral agents effectively induce viral suppression, which is accompanied by an improvement in transaminases and hepatic histology. Nonetheless, the rates of HBe and HBs seroconversion remain low with nucleoside analogs, and the absence of these immunologic events necessitates prolonged antiretroviral treatment. Treatment with nucleoside analogs leads to selection of resistant mutant viruses. They therefore require close clinical and virologic follow-up to enable early screening for resistance and adaptation of treatment before the liver disease worsens. The development of these different treatment options has made possible very significant improvements in the management of patients with chronic hepatitis B, by preventing aggravation of liver disease in most of them.