Antiviral drug resistance now poses a major problem for the management of patients with chronic hepatitis B. In theory, resistance may be prevented if a sufficiently potent antiviral drug, or combination of antiviral agents, is used that prevents viral replication and thereby the ongoing selection of hepatitis B virus quasispecies. Emergence of drug resistance in patients with hepatitis B generally results in progression of liver disease and in some cases, significant clinical deterioration if hepatic reserve is compromised. Currently, there are two major patterns of resistance mutations found in the viral reverse transcriptase (rt) that can be selected during monotherapy: (1) those that include the codon rtM204, which is part of the catalytic domain (YMDD) of the enzyme; (2) and those that do not include the codon. The rtM204I/V is selected by lamivudine and l-nucleosides. It is also part of the entecavir resistance profile and the tenofovir-lamivudine combination resistance profile. In contrast, resistance to adefovir is associated with mutations at rtN236T ± rtA181V. A reasonable clinical goal is to develop an overall strategy that prevents the selection of resistance. These strategies have yet to be optimized for hepatitis B, but may include multiple therapies such as immune-based therapies in combination with one or more nucleoside analogue treatments. Future treatment protocols can be modeled on the use of multiple agents comprising highly active anti-retroviral therapy regimens that have been developed for the successful management of patients infected with human immunodeficiency virus.