In successful antiviral therapy of hepatitis B, drug combinations, particularly combinations without cross-resistance, can delay or prevent the emergence of drug-resistant mutants. Because drug-resistant mutants are archived and may limit future therapeutic options, prevention is important for long-term therapeutic efficacy. Additionally, combining drugs may achieve synergistic or additive antiviral effects compared with single drug therapy. Undesirable aspects of combination therapy include higher treatment costs and possibly lower adherence rates (due to pill number or complexity of regimen). Potentially harmful effects of combination therapy include higher rates of side effects, reduced efficacy due to drug competition, and the risk of multidrug-resistant hepatitis B virus (HBV) if combination therapy is insufficient to prevent resistance. Combination therapy has been shown to reduce the rate of drug resistance in chronic hepatitis B, but only when drugs with a low barrier to resistance are used (lamivudine, adefovir). Combination therapies may achieve greater degrees of HBV DNA suppression, but this has not been associated with higher rates of seroconversion (hepatitis B e antigen or hepatitis B surface antigen) compared to single drug therapy. The benefit of combination therapy has yet to be demonstrated with agents that are associated with a high barrier to resistance (tenofovir, entecavir). The use of combination therapy is recommended in specific patient groups: those with decompensated cirrhosis, those coinfected with human immunodeficiency virus and HBV who are on antiretroviral therapy, those who have undergone liver transplantation, and those with drug-resistant HBV infection. There is insufficient evidence to recommend combination therapy as first-line therapy for all patients with chronic hepatitis B. (HEPATOLOGY 2009;49:S122-S128.