Current strategies for treating hepatitis B focus on clearance of active HBV infection through suppression of viral replication by interferon-alpha (IFN-alpha) and the nucleoside analogs (lamivudine and adefovir). Lamivudine therapy for 1 year leads to HBeAg seroconversion in 16-18% of patients compared to 4-6% of untreated controls, to histological improvement in 49-56% treated patients and in 23-25% controls. HBeAg seroconversion rates increase with the duration of lamivudine therapy from 17% at 1 year to 27, 40, 47 and 50% at 2, 3, 4 and 5 years, respectively. When prescribing lamivudine, drug resistance due to the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) mutations that increases with duration of therapy and the potential risk of a severe flare of hepatitis with sudden cessation of therapy, probably greatest in patients with cirrhosis, are realistic concerns. After 48 weeks of treatment with 10 or 30 mg of adefovir dipivoxil per day, significantly more patients with HBeAg-positive chronic hepatitis B than those on placebo had histologic improvement (53, 59 and 25%, respectively), a reduction in serum HBV DNA levels (by a median of 3.52, 4.76 and 0.55 log copies/ml), undetectable levels of serum HBV DNA (21, 39 and 0%), normalisation of ALT levels (48, 55 and 16%) and HBeAg seroconversion (12, 14 and 6%). In HBeAg negative patients treated with adefovir dipivoxil (10mg/day) for 48 weeks, ALT levels had normalised in 72% (29% in the placebo group), serum HBV DNA levels were reduced to fewer than 400 copies/ml in 51% (none in the placebo group), liver histology improved in 64% (33% in the placebo group). No adefovir-associated resistance mutations of viral DNA were detected. Ongoing studies investigate combination therapy with lamivudine or IFN.