The last decade has witnessed substantial progress in the development of chemotherapeutic agents for chronic hepatitis B. However, the only currently licensed treatment in Australia, interferon-alpha, has low initial response rates and the adverse effects are often unacceptable. Of the newer agents in the class of nucleoside analogues, famciclovir and lamivudine are in phase III clinical trials with encouraging preliminary results, while other agents, such as bis-POM PMEA (Adefovir), are at phase I/II development. Future approaches to therapy will be governed by an understanding of the effects of nucleoside analogues on the natural history of the disease as well as on the hepatitis B virus hepatocyte interaction. Combination antiviral therapy should theoretically offer improved response rates, decrease the development of viral resistance, and provide the greatest reduction in viral load, but it has not yet been widely examined in the clinical setting. In this article, we review the currently available strategies, discuss potential problem areas, and speculate on promising approaches with combination chemotherapy and the features of agents soon to be trialed.