The clinical management of chronic hepatitis B infection has entered a new era with the introduction and widespread use of oral nucleoside analogues such as lamivudine and nucleotides such as adefovir dipivoxil. From this, new challenges have now emerged in terms of preventing antiviral drug resistance, promoting viral clearance and improving long-term survival. For example, the natural history of nucleoside or nucleotide analogue-associated hepatitis B virus resistant mutants has yet to be determined. Furthermore, the increasing prevalence of HBeAg negative disease with its reduced response to current therapies represents an ongoing challenge to attempts to improve standard of care. There is increasing recognition of the pivotal role that viral load and genotype, and their complex interactions with the host immune response, play in determining the outcome of these treatment interventions. The purpose of this paper is to highlight several key factors that should be considered in the context of future clinical research and management of chronic hepatitis B. Copyright © 2003 John Wiley & Sons, Ltd.