Nucleos(t)ide analogs (NAs) have become the mainstream drugs for the treatment of chronic hepatitis B virus infection. Drug resistance to NAs, however, has posed a major obstacle in obtaining sustained viral suppression. Standardized definitions of terms and nomenclature in discussing NAs resistance have been proposed. Drug resistance to NAs is produced by a combination of viral, host and antiviral drug factors. A detailed understanding of the mechanisms and effects of mutation sites that cause resistance to NAs is important for the design of rational treatment and management of patients with existing drug resistance.