Chronic hepatitis B virus (HBV) infection is one of the major health care burdens throughout the world. The chronicity of HBV infection is supported by the intracellular persistence of a multicopy viral episome called covalently closed circular DNA (cccDNA), which is the bona fide viral transcription template and resistant to currently available antivirals. Therefore, noncytolytic elimination of cccDNA is considered as the "holy grail" for a cure of hepatitis B, and the metabolism and transcription regulation of cccDNA have become a hot topic in basic, translational, and clinical HBV research.