The development of nucleoside analogues has been a major advance in the treatment of hepatitis B; however, prolonged monotherapy is associated with drug resistance. Currently, no data in humans indicate that a combination of nucleoside analogues leads to enhanced efficacy. New nucleoside analogues with greater inhibitory effects on hepatitis B virus (HBV) replication being developed could prove to be more effective or less likely to be associated with viral resistance. Interferon still has a role to play in the management of chronic HBV infection. Recent data indicate that the response to interferon may be determined in part by differences in genotype. From a theoretical perspective, a combination of pegylated interferon with one or more nucleosides could induce a higher rate of virological response. Additional studies are needed to further address these issues.