Currently, there are 7 approved therapies for chronic hepatitis B virus (HBV) infection, an increase from just 3 agents 5 years ago. This review will focus on the pharmacology, potency, and adverse events associated with immunomodulatory agents and nucleos(t)ide analogues, with an emphasis on targets of therapy within the HBV life cycle. We will also offer guidelines for the use of available anti-HBV agents and review the emerging challenges in hepatitis B management, including HBV drug resistance, its management, and the potential role of combination therapy.