Treatment of chronic hepatitis B virus (HBV) infection currently involves the use of immunomodulators such as interferon and nucleoside or nucleotide analogues. Treatment aims to suppress levels of HBV DNA and induce clearance of the hepatitis B e antigen (HBeAg) or surface antigen (HBsAg) and seroconversion. At present, no single treatment has been shown to reliably suppress HBV DNA and induce durable HBsAg loss. Nucleoside or nucleotide analogues induce the production of HBV-resistant mutations that may lead to virologic and clinical breakthrough. Combination therapy, using either immunomodulators in combination or with nucleoside or nucleotide analogues, represents an emerging strategy for treating chronic HBV infection. The theoretical benefits of combining agents with varying mechanisms of action include more efficacious viral suppression and potentially durable HBsAg loss. Although combination therapy has proven successful in chronic hepatotropic viral infections and in chronic, noninfectious medical conditions, its benefits must be weighed against risks such as increased toxicity, resistance, and cost.