Significant progress has been made during the last 2 years in the treatment of chronic hepatitis B (CHB). Treatment decisions differ significantly depending on whether patients are HBeAg+ or HBeAg-, treatment-naive or nucleoside/nucleotide-resistant, and in early or advanced stages of liver disease. Courses of finite duration, aiming to achieve sustained off-therapy responses, are practically restricted to HBeAg+ patients with compensated chronic liver disease, whereas long-term therapy aiming to achieve maintained on-therapy remission is mostly applicable to HBeAg- individuals either with early or advanced liver disease. A course of finite duration with pegylated (PEG)-IFN-alpha-2a offers the highest probability of sustained off-therapy response in HBeAg+ individuals, as well as in some HBeAg- individuals. Long-term therapy with nucleoside/nucleotide analogues, both in HBeAg+ and HBeAg- CHB, has most favourable effects on patient outcome, provided that virological and biochemical remission is maintained without development of viral resistance. The best results are achievable with potent analogues suppressing serum hepatitis B virus (HBV) DNA to non-detectability by most sensitive techniques. The best 2-year resistance profile has hitherto been reported with entecavir monotherapy, and the best long-term resistance profile was seen with adefovir of 5-year duration. Adefovir is effective in most lamivudine (LAM)-resistant patients, but should be administered as an add-on rather than as a substitute for LAM. Combination therapies have entered the treatment arena of CHB by the side doors of LAM-resistance and of end-stage liver disease, and the most recent results suggest that treatment with combinations of two strong nucleosides/nucleotides with different resistance profiles may turn out to be the optimal first-line/first choice option in CHB.