Chronic hepatitis B virus (HBV) infections remain a major public health problem worldwide. According to World Health Organization estimates, more than 300 million people are chronically infected and exposed to the risk of developing severe complications including cirrhosis and hepatocellular carcinoma (HCC). Major progress in the treatment of chronic hepatitis B (CHB) has been made during the last decade with the development of antivirals that inhibit viral polymerase activity. Antiviral drug resistance is an important factor in determining the success of long-term therapy for CHB. The development of resistance to nucleoside analogues (NUCs) has been associated with exacerbations of liver disease. Sequential therapy increases the risk of the emergence of multidrug resistance. The selection of a potent antiviral with a high barrier to resistance as a first-line therapy provides the best chance of achieving long-term treatment goals and should be used whenever possible. This has led to a significant decrease in drug resistance in countries where this strategy is affordable. However, the barrier to resistance of a given antiviral agent is influenced by the genetic barrier, drug potency, patient adherence, pharmacological barrier, viral fitness, the drug mechanisms of action and cross resistance. Furthermore, because of specific viral kinetics, prolonged treatment with NUCs does not result in the clearance of the viral genome from the infected liver. It is therefore important to continue research to identify new viral and immune targets and develop novel antiviral strategies for controlling viral replication as well as preventing drug resistance and its complications in the long term.