Despite the accumulating knowledge, chronic hepatitis B (CHB) and HDV infection represent a global health problem, and there are still several critical issues, which frequently remain uncovered. In this paper, we provided an overview of the current therapeutic options and summarized the investigational therapies in the pipeline. Furthermore, we discussed some critical issues such as a “functional cure” approach, the futility of long-term NA therapy and the relevance of understanding drug actions and safety of antivirals, especially in special populations.