Chemotherapy for chronic hepatitis B virus (HBV) infection is inherently difficult for a variety of reasons that are related to unusual features of both HBV replication strategy and host cell metabolism. Previous attempts to treat chronic HBV infection using nucleoside analogues have been almost universally disappointing, but several recently developed nucleoside analogues have been identified as potent, non-toxic inhibitors of HBV replication. These fall into two broad categories: nucleosides having the ‘unnatural’L-configuration, and deoxyguanosine analogues with modified-sugar configurations, represented by lamivudine and penciclovir respectively. Both lamivudine and penciclovir (in its orally available form, famciclovir) have progressed to phase III clinical trials against chronic HBV infection, with promising preliminary results. However, chemotherapy for chronic HBV is necessarily long term, which increases the risks for development of viral resistance and cumulative toxicity. Such risks might be minimized by the use of appropriate drug combinations, rational selection of which requires knowledge of the pharmacokinetics and mechanisms of action of the individual agents. An appreciation of cellular deoxynucleoside metabolism and its regulation, the complexities of which are still emerging, is an indispensable aid to understanding the biological activities of deoxynucleoside analogues. The modes of action of lamividine and penciclovir, and how these two deoxynucleoside analogues may interact in vitro and in vivo as inhibitors of HBV replication, are examined here in the context of cellular deoxynucleoside metabolism.