Hepatitis B virus (HBV) infection remains a major public health problem worldwide. Recently, the research efforts to identify new inhibitors enabled the development of antiviral agents to treat patients chronically infected by HBV. In clinical practice, the use of nucleoside analogs, which inhibit viral polymerase activity, induces suppression of viral replication accompanied by an improvement in biochemical and histological conditions in most patients. However, many clinical studies revealed the emergence of drug-resistant mutants during extended treatment. This review focuses on the mechanism of HBV drug-resistant mutant selection and on the clinical implications of HBV drug resistance for the prevention of treatment failure.