In the last years, marked progress has been made in the treatment of chronic hepatitis B. The efficacy of lamivudine, the first nucleoside analogue available, is limited by the high incidence of resistance. Adefovir, which was recently approved has a comparable efficacy with a very low frequency of resistance. However, adefovir needs to be indefinitely administered as withdrawal of therapy is generally associated with reactivation and sustained response is uncommon. Recent large randomized controlled trials showed that PEG IFNs induce relatively high sustained response rates both in HBeAg positive and HBeAg negative 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 assessed 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 at various stages of clinical development. Results of phase III trials of entecavir and emtricitabine confirmed their efficacy. However, while entecavir is associated with a low incidences of resistance, emtricitabine is associated with a relatively high incidence of resistance which limits its use as a monotherapy. The efficacy and safety of new and more potent drugs like telbivudine and clevudine need to be confirmed. 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 different sites of action on HBV DNA replication, a potent antiviral effect, an excellent safety profile and they should induce a sustained response with a limited duration of therapy. 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 few combinations have been evaluated. No combination therapy demonstrated a benefit as compared with monotherapy. More potent drugs and new combinations together with the understanding of the mechanisms of resistance to therapy are important challenges to improve the efficacy of treatment and decrease in the future the global burden related to chronic hepatitis B.