The goal of hepatitis B treatment is to prevent cirrhosis, liver decompensation and hepatocellular carcinoma. In clinical practice, treatment response is determined by suppression of serum HBV DNA levels, hepatitis B e antigen seroconversion to hepatitis B e antibody, hepatitis B surface antigen loss, normalization of alanine aminotransferase levels and improvement in liver histology. Patients with life-threatening liver disease, and those with high levels of HBV replication and active or advanced liver disease, should be treated. Other patients should be monitored so that treatment can be initiated when indicated. Currently, seven medications are approved for the treatment of hepatitis B: two formulations of interferon and five nucleos(t)ide analogues. Interferon is administered for a finite duration while nucleos(t)ide analogues are usually administered for many years. Antiviral drug resistance is a major limiting factor to the success of nucleos(t)ide analogue treatment; therefore, treatment should be initiated with drugs that have a high genetic barrier to resistance (that is, a low potential for drug resistance). In addition, treatment response should be closely monitored to detect virologic breakthroughs, and the importance of medication adherence should be emphasized. Management of patients with treatment failure should be tailored according to the type of treatment failure (lack of initial response versus virologic breakthrough), the treatment that the patient is receiving, history of prior treatment, and the pretreatment characteristics of both the patient and the disease.