In recent years, marked progress has been made in the treatment of chronic viral hepatitis. Recent studies suggest that pegylated interferons (PEG IFNs) are more effective than standard IFNs in the treatment of chronic hepatitis B. So far, the combination of PEG IFN with lamivudine, used simultaneously, is disappointing in terms of short-term efficacy. However, long-term efficacy needs to be addressed and different schedules of combination, for example sequential, need to be evaluated. A number of nucleoside analogues, with favourable toxicity profiles and a promise of increased effectiveness against HBV, are in various stages of clinical development. Entecavir has recently been approved in the USA. The future of chronic hepatitis B therapy seems to be in the combination of different drugs. Ideally, the optimal drugs to combine would meet the following criteria: they should have a potent antiviral effect, an excellent safety profile and the duration of therapy should be limited. Indeed, the concept of combination therapy has been recently developed in order to increase efficacy and to decrease the occurrence of viral resistance. However, so far there are few data available and no combination therapy demonstrated a clear benefit as compared with monotherapy. More potent drugs and new combinations together with the understanding of the mechanisms of resistance to therapy are challenges to improve the efficacy of treatment and decrease in the future the global burden related to chronic hepatitis B.