Treatment options for chronic HBV infection have improved considerably in recent years. However, with the increased number of available antiviral drugs, it is also more difficult to select the optimal drug for each individual patient. Antiviral potency, the risk for the development of drug resistance, safety and costs of treatment all need to be considered. In this review, we describe current concepts in the treatment of chronic hepatitis B, with a special focus on the importance of drug resistance and its implications for the long-term management of hepatitis B. Suggestions for avoiding resistance and management of established drug resistance are provided for each individual approved compound.