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Chronic hepatitis B remains a significant cause of morbidity and mortality worldwide. Most hepatitis B virus (HBV)-infected individuals are neither diagnosed nor treated. In those treated, nucleos(t)ide polymerase inhibitors persistently suppress viremia to the limits of quantitation; however, few achieve a "functional cure," defined as sustained off-treatment loss of detectable serum HBV DNA with or without loss of hepatitis B surface antigen. The low cure rate has been attributed to an inability to eliminate the viral reservoir of covalently closed circular DNA from hepatocytes. This review focuses on the diverse therapeutic approaches currently under development that may contribute to the goal of HBV cure.