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Chronic hepatitis B (CHB) remains a significant unmet medical need, with 240 million chronically infected persons worldwide. It can be controlled effectively with either nucleoside/nucleotide-based or interferon-based therapies. However, most patients receiving these therapies will relapse after treatment withdrawal. During recent years, the advances in molecular biology and immunology have enabled a better understanding of the viral-host interaction and inspired new treatment approaches to achieve either elimination of the virus from the liver or durable immune control of the infection. This review aims to provide a brief overview on the potential new therapies that may overcome the challenge of persistent CHB infection in the near future.