Chronic Hepatitis B Virus (HBV) infection remains a worldwide concern and continues to be a global public health problem. Two key aspects of the HBV life cycle are essential for viral replication and thus the development of chronic infections: the establishment of the viral minichromosome, covalently closed circular (ccc) DNA, within the nucleus of infected hepatocytes, and the expression of the regulatory protein HBx. Interestingly, nuclear HBx redirects host epigenetic machinery to activate cccDNA transcription. In this Perspective, we provide an overview of recent advances in understanding the regulation of cccDNA and mechanistic and functional roles of HBx. We also describe the progress toward targeting both cccDNA and HBx for therapeutic purposes. Finally, we outline standing questions in the field and propose complementary chemical biology approaches to address them.